Publications by authors named "Yuko Aoki"

49 Publications

Convolutional neural network for classification of two-dimensional array images generated from clinical information may support diagnosis of rheumatoid arthritis.

Sci Rep 2020 03 27;10(1):5648. Epub 2020 Mar 27.

Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.

This research aimed to study the application of deep learning to the diagnosis of rheumatoid arthritis (RA). Definite criteria or direct markers for diagnosing RA are lacking. Rheumatologists diagnose RA according to an integrated assessment based on scientific evidence and clinical experience. Our novel idea was to convert various clinical information from patients into simple two-dimensional images and then use them to fine-tune a convolutional neural network (CNN) to classify RA or nonRA. We semi-quantitatively converted each type of clinical information to four coloured square images and arranged them as one image for each patient. One rheumatologist modified each patient's clinical information to increase learning data. In total, 1037 images (252 RA, 785 nonRA) were used to fine-tune a pretrained CNN with transfer learning. For clinical data (10 RA, 40 nonRA), which were independent of the learning data and were used as testing data, we compared the classification ability of the fine-tuned CNN with that of three expert rheumatologists. Our simple system could potentially support RA diagnosis and therefore might be useful for screening RA in both specialised hospitals and general clinics. This study paves the way to enabling deep learning in the diagnosis of RA.
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http://dx.doi.org/10.1038/s41598-020-62634-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101306PMC
March 2020

Improving Low-contrast Detectability and Noise Texture Pattern for Computed Tomography Using Iterative Reconstruction Accelerated with Machine Learning Method: A Phantom Study.

Acad Radiol 2020 07 7;27(7):929-936. Epub 2020 Jan 7.

Department of Diagnostic Radiology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

Rationale And Objectives: To evaluate the performance of iterative reconstruction (IR) and filtered back projection (FBP) images in terms of low-contrast detectability at different radiation doses, IR levels, and slice thickness using the mathematical model observer with a focus on low-contrast detectability.

Materials And Methods: The CCT189 MITA CT IQ Low-Contrast Phantom was used and helical scans were performed using a 64-detector CT scanner. Tube voltage was set at 120 kVp and tube current was adjusted from 45 to 600 mA. Images were reconstructed at slice thicknesses of 0.625 and 5.0 mm with FBP and five types of iterative progressive reconstruction with visual modeling (IPV) algorithms. The noise power spectrum (NPS) and normalized NPS were calculated. To evaluate low-contrast detectability, the model observer with the channelized Hotelling observer model was applied using low-contrast modules in the phantom.

Results: The NPS and normalized NPS for IPV images had similar curves as that for FBP images. At a slice thickness of 0.625 mm and equivalent radiation dose level, the mean improvement of low-contrast detectability for IPV images was 1.19-2.15-fold greater than FBP images with corresponding noise reduction levels. At equivalent noise levels of 5.0-8.0 HU, low-contrast detectability of the IPVstd2 to IPVstr2 images as almost the same or better than that of the FBP images. However, the detectability of the IPVstr4 image was lower than that of the FBP image (p = 0.02).

Conclusion: Low-contrast detectability of the IPV images was improved with a similar normalized NPS as with FBP images. Furthermore, a radiation reduction of >50% was achieved for the IPV images, while maintaining similar low-contrast detectability.
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http://dx.doi.org/10.1016/j.acra.2019.09.007DOI Listing
July 2020

No Evidence for Particular Association Between HLA-Haploidentical Hematopoietic Stem Cell Transplantation and Psychological Distress.

Transplant Proc 2019 Jul - Aug;51(6):1990-1993. Epub 2019 Jul 11.

Department of Psychiatry, Tokyo Women's Medical University, Tokyo, Japan.

Background: The psychological distress experienced by patients scheduled for hematopoietic stem cell transplantation (HSCT) is of clinical concern. However, distress experienced by patients scheduled for HLA-haploidentical HSCT vs that of patients scheduled for other types of matched HSCT is unknown. We conducted a retrospective study to clarify whether the type of HSCT influences the appearance of psychological distress in patients anticipating HSCT.

Methods: One hundred fifty-seven patients who had undergone any of 4 types of HSCT at Tokyo Metropolitan Komagome Hospital between October 2013 and September 2016 and had completed the Profile of Mood States (POMS) questionnaire within 2 weeks before the procedure were included. We computed T-scores for the tension-anxiety (TA) and depression (D) subscales, took scores ≥ 60 to represent mood disturbance of clinical concern, and examined scores and other clinical variables in relation to each procedure.

Results: Twenty-two (14.0%) patients had a POMS-TA score ≥ 60, and 26 (16.6%) had a POMS-D score ≥ 60. The numbers of POMS-TA and POMS-D scores  ≥ 60 did not differ significantly with respect to age, sex, leukemia type, number of previous transplants, disease status, comorbidity index, or transplant type. A multivariate logistic regression analysis confirmed the absence of an influence of the type of HSCT on the incidence of POMS-TA or POMS-D scores ≥60.

Conclusion: Attention should be paid to the matter of psychological distress in patients with leukemia who will be treated by HSCT, even HLA-haploidentical HSCT. Such patients need psychological support, especially during the waiting period immediately prior to the transplantation procedure.
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http://dx.doi.org/10.1016/j.transproceed.2019.03.029DOI Listing
November 2019

Japanese traditional herbal medicine reduces use of pregabalin and opioids for pain in patients with lumbar spinal canal stenosis: a retrospective cohort study.

JA Clin Rep 2017 27;3(1):60. Epub 2017 Oct 27.

Department of Anesthesiology, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka-shi, Iwate, 020-8505 Japan.

Background: There has been an increase in the number of Japanese patients with lumbar spinal canal stenosis (LSCS) who complain of chronic pain or motor disturbance in the lower back or extremities. These patients are often treated with anti-convulsive drugs, opioids, antidepressants, acetaminophen, or nonsteroidal anti-inflammatory drugs, all of which can cause side effects. For this reason, Japanese traditional herbal medicine (Kampo) is of interest, because it produces fewer adverse reactions. The aim of this retrospective cohort study was to analyze the effects of Kampo in patients with LSCS.

Findings: A total of 151 patients with LSCS were divided into two groups based on treatment with ( = 111, group K) and without ( = 40, group N) Kampo. Use of pregabalin and opioids decreased significantly in group K ( < 0.001). The hazard ratio for opioid discontinuation was 0.220 ( = 0.004) for group N vs. group K, while that for pregabalin and antidepressants discontinuation were 0.589 ( = 0.202) and 0.509 ( = 0.377), respectively. The mean duration of hospital visits and treatment did not differ between the groups, but the number of dropouts was significantly higher in group N ( < 0.0001). The hazard ratio for patient dropout was 4.118 ( = 0.001) for group N vs. group K.

Conclusions: Kampo led to discontinuation of opioid use for pain in patients with LSCS, and patients who were treated with Kampo were more likely to continue treatment.
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http://dx.doi.org/10.1186/s40981-017-0130-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804655PMC
October 2017

Computer-Based Radiographic Quantification of Joint Space Narrowing Progression Using Sequential Hand Radiographs: Validation Study in Rheumatoid Arthritis Patients from Multiple Institutions.

J Digit Imaging 2017 Oct;30(5):648-656

Hokkaido Medical Center for Rheumatic Diseases, 1-45 3-Chome, 1-Jo, Kotoni, Nishi-ku, Sapporo, 063-0811, Japan.

We have developed a refined computer-based method to detect joint space narrowing (JSN) progression with the joint space narrowing progression index (JSNPI) by superimposing sequential hand radiographs. The purpose of this study is to assess the validity of a computer-based method using images obtained from multiple institutions in rheumatoid arthritis (RA) patients. Sequential hand radiographs of 42 patients (37 females and 5 males) with RA from two institutions were analyzed by a computer-based method and visual scoring systems as a standard of reference. The JSNPI above the smallest detectable difference (SDD) defined JSN progression on the joint level. The sensitivity and specificity of the computer-based method for JSN progression was calculated using the SDD and a receiver operating characteristic (ROC) curve. Out of 314 metacarpophalangeal joints, 34 joints progressed based on the SDD, while 11 joints widened. Twenty-one joints progressed in the computer-based method, 11 joints in the scoring systems, and 13 joints in both methods. Based on the SDD, we found lower sensitivity and higher specificity with 54.2 and 92.8%, respectively. At the most discriminant cutoff point according to the ROC curve, the sensitivity and specificity was 70.8 and 81.7%, respectively. The proposed computer-based method provides quantitative measurement of JSN progression using sequential hand radiographs and may be a useful tool in follow-up assessment of joint damage in RA patients.
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http://dx.doi.org/10.1007/s10278-017-9970-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603443PMC
October 2017

Active synovitis in the presence of osteitis predicts residual synovitis in patients with rheumatoid arthritis with a clinical response to treatment.

Int J Rheum Dis 2018 Oct 3;21(10):1809-1814. Epub 2017 Feb 3.

Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Aim: To clarify the relationship between active synovitis/osteitis and subsequent residual synovitis (R-synovitis) in patients with rheumatoid arthritis (RA).

Methods: Three hundred and twenty finger joints of 16 patients with active RA at baseline (Disease Activity Score with 28 joints - erythrocyte sedimentation rate > 3.2) who subsequently achieved clinical low disease activity or remission afterwards were analyzed. Synovial vascularity (SV) was assessed according to a semi-quantitative ultrasound score (grades 0-3). Active synovitis was defined by SV positivity at baseline. R-synovitis was defined by the presence of grade > 2 SV at the 24th week. Osteitis was detected by magnetic resonance imaging (MRI) at baseline as trabecular bone lesions with water content and indistinct margins.

Results: Ultrasonography detected active synovitis in 116 joints at baseline. Forty-seven joints had R-synovitis at the 24th week. MRI detected osteitis in 12 joints at baseline. The presence of active synovitis with osteitis at baseline was significantly correlated with R-synovitis at the 24th week.

Conclusions: Active synovitis in the presence of osteitis predicted R-synovitis regardless of whether there was a clinical improvement in RA.
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http://dx.doi.org/10.1111/1756-185X.13030DOI Listing
October 2018

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor.

Mol Cancer Ther 2015 Dec 5;14(12):2831-9. Epub 2015 Oct 5.

Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.

Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0497DOI Listing
December 2015

Somatic copy number alterations associated with Japanese or endometriosis in ovarian clear cell adenocarcinoma.

PLoS One 2015 6;10(2):e0116977. Epub 2015 Feb 6.

Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan.

When compared with other epithelial ovarian cancers, the clinical characteristics of ovarian clear cell adenocarcinoma (CCC) include 1) a higher incidence among Japanese, 2) an association with endometriosis, 3) poor prognosis in advanced stages, and 4) a higher incidence of thrombosis as a complication. We used high resolution comparative genomic hybridization (CGH) to identify somatic copy number alterations (SCNAs) associated with each of these clinical characteristics of CCC. The Human Genome CGH 244A Oligo Microarray was used to examine 144 samples obtained from 120 Japanese, 15 Korean, and nine German patients with CCC. The entire 8q chromosome (minimum corrected p-value: q = 0.0001) and chromosome 20q13.2 including the ZNF217 locus (q = 0.0078) were amplified significantly more in Japanese than in Korean or German samples. This copy number amplification of the ZNF217 gene was confirmed by quantitative real-time polymerase chain reaction (Q-PCR). ZNF217 RNA levels were also higher in Japanese tumor samples than in non-Japanese samples (P = 0.027). Moreover, endometriosis was associated with amplification of EGFR gene (q = 0.047), which was again confirmed by Q-PCR and correlated with EGFR RNA expression. However, no SCNAs were significantly associated with prognosis or thrombosis. These results indicated that there may be an association between CCC and ZNF217 amplification among Japanese patients as well as between endometriosis and EGFR gene amplifications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319764PMC
May 2016

CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

Int J Oncol 2015 Apr 30;46(4):1560-72. Epub 2015 Jan 30.

Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.
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http://dx.doi.org/10.3892/ijo.2015.2860DOI Listing
April 2015

The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor.

Mol Cancer Ther 2014 Nov 28;13(11):2547-58. Epub 2014 Aug 28.

Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.

The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0248DOI Listing
November 2014

Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor-4.

Cancer Sci 2014 Oct 25;105(10):1343-50. Epub 2014 Sep 25.

Research Division, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.

Rhabdomyosarcoma is the most common soft tissue sarcoma affecting children, and the overall cure rate of children with metastatic disease remains below 30%. The CXC chemokine receptor-4 (CXCR4)/stromal cell-derived factor-1 (SDF1) axis has been implicated in the promotion of metastatic potential in several tumors. In this study, we developed a novel anti-CXCR4 mAb, CF172, and investigated its antimetastatic activity against rhabdomyosarcoma cells in vitro and in vivo, to evaluate its potential as a therapeutic antibody to treat rhabdomyosarcoma. The CF172 molecule showed a specific binding reactivity against human CXCR4, as well as a specific neutralizing activity against CXCR4/SDF1 signal transduction. Using CF172, we determined that SJCRH30 rhabdomyosarcoma cells expressed high levels of CXCR4. In addition, CF172 was found to inhibit the SDF1-induced migration activity of SJCRH30 cells in vitro. Using xenograft models of SJCRH30 cells, we carried out in vivo efficacy studies for peritoneal and lymph node metastasis, which were clinically observed in rhabdomyosarcoma. These studies indicated that CF172 significantly decreased both types of metastasis of SJCRH30. In conclusion, we found that a novel anti-CXCR4 mAb, CF172, with specific reactivity against human CXCR4, prevented peritoneal metastasis and lymph node metastasis of rhabdomyosarcoma in animal models. These results suggest that CF172 is a potential antimetastasis therapeutic antibody for rhabdomyosarcoma treatment.
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http://dx.doi.org/10.1111/cas.12490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462355PMC
October 2014

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.

ACS Med Chem Lett 2014 Apr 22;5(4):309-14. Epub 2014 Jan 22.

Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan ; Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.

Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.
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http://dx.doi.org/10.1021/ml400379xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027752PMC
April 2014

Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties.

ACS Med Chem Lett 2013 Nov 22;4(11):1059-63. Epub 2013 Sep 22.

Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan ; Research Division, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.

A facile methodology effective in obtaining a set of compounds monofluorinated at various positions (fluorine scan) by chemical synthesis is reported. Direct and nonselective fluorination reactions of our lead compound 1a and key intermediate 2a worked efficiently to afford a total of six monofluorinated derivatives. All of the derivatives kept their physicochemical properties compared with the lead 1a and one of them had enhanced Raf/MEK inhibitory activity. Keeping physicochemical properties could be considered a benefit of monofluorinated derivatives compared with chlorinated derivatives, iodinated derivatives, methylated derivatives, etc. This key finding led to the identification of compound 14d, which had potent tumor growth inhibition in a xenograft model, excellent PK profiles in three animal species, and no critical toxicity.
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http://dx.doi.org/10.1021/ml4002419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027529PMC
November 2013

The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors.

Bioorg Med Chem Lett 2013 Dec 9;23(23):6223-7. Epub 2013 Oct 9.

Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.

Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC50=8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED50=4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment.
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http://dx.doi.org/10.1016/j.bmcl.2013.10.001DOI Listing
December 2013

Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non-small-cell lung cancer.

Cancer Sci 2013 Oct 20;104(10):1346-52. Epub 2013 Aug 20.

Discovery Pharmacology Department 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan.

Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of multiple client proteins, which are involved in tumor progression. Epidermal growth factor receptor (EGFR) is one of the most potent oncogenic client proteins of Hsp90. Targeted inhibition of EGFR has shown clinical efficacy in the treatment of patients with non-small-cell lung cancer (NSCLC). However, primary and acquired resistance to the existing EGFR inhibitors is a major clinical problem. In the present study, we investigated the effect of the novel Hsp90 inhibitor CH5164840 on the antitumor activity of erlotinib. The NSCLC cell lines and xenograft models were treated with CH5164840 and erlotinib to examine their mechanisms of action and cell growth inhibition. We found that CH5164840 showed remarkable antitumor activity against NSCLC cell lines and xenograft models. The addition of CH5164840 enhanced the antitumor activity of erlotinib against NCI-H292 EGFR-overexpressing xenograft models. Phosphorylation of Stat3 increased with erlotinib treatment in NCI-H292 cells, which was abrogated by Hsp90 inhibition. Furthermore, in a NCI-H1975 T790M mutation erlotinib-resistant model, CH5164840 enhanced the antitumor activity of erlotinib despite the low efficacy of erlotinib treatment alone. In addition, ERK signaling was effectively suppressed by combination treatment with erlotinib and CH5164840 in a NCI-H1975 erlotinib-resistant model. Taken together, these data indicate that CH5164840 has potent antitumor activity and is highly effective in combination with erlotinib against NSCLC tumors with EGFR overexpression and mutations. Our results support the therapeutic potential of CH5164840 as a Hsp90 inhibitor for combination therapy with EGFR-targeting agents against EGFR-addicted NSCLC.
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http://dx.doi.org/10.1111/cas.12237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656539PMC
October 2013

A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes.

Gastroenterology 2013 Oct 18;145(4):865-73. Epub 2013 Jun 18.

Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Research Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

Background & Aims: Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice.

Methods: We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors.

Results: NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors.

Conclusions: The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors.
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http://dx.doi.org/10.1053/j.gastro.2013.06.012DOI Listing
October 2013

Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.

Cancer Res 2013 Jul 10;73(13):4050-4060. Epub 2013 May 10.

Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Tumors with mutant RAS are often dependent on extracellular signal-regulated kinase (ERK) signaling for growth; however, MEK inhibitors have only marginal antitumor activity in these tumors. MEK inhibitors relieve ERK-dependent feedback inhibition of RAF and cause induction of MEK phosphorylation. We have now identified a MEK inhibitor, CH5126766 (RO5126766), that has the unique property of inhibiting RAF kinase as well. CH5126766 binding causes MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF. This results in formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, this drug does not induce MEK phosphorylation. CH5126766 inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity as well. These results suggest that relief of RAF feedback limits pathway inhibition by standard MEK inhibitors. CH5126766 represents a new type of MEK inhibitor that causes MEK to become a dominant-negative inhibitor of RAF and that, in doing so, may have enhanced therapeutic activity in ERK-dependent tumors with mutant RAS.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115369PMC
July 2013

Enantioselective synthesis of derivatives and structure-activity relationship study in the development of NA255 as a novel host-targeting anti-HCV agent.

Bioorg Med Chem Lett 2013 Jan 30;23(1):336-9. Epub 2012 Oct 30.

Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Electronic address:

Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed. The structure-activity relationship of the NA255 derivatives and rat pharmacokinetic profiles of the representative compounds are disclosed.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.083DOI Listing
January 2013

Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D.

Cancer Sci 2012 Dec 30;103(12):2144-52. Epub 2012 Oct 30.

Department 2 of Pharmaceutical Research, Chugai Pharmaceutical Co. Ltd, Kanagawa, Japan.

Lymphatic spread is an important clinical determinant in the prognosis of many human cancers. The lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) is implicated in the promotion of lymphatic metastasis through the development of lymphatic vessels in some human cancers. In this study, we developed an anti-VEGF-D monoclonal antibody, cVE199, and investigated its in vitro properties, in vivo effects against tumors and possible target indications to evaluate its potential as a therapeutic antibody. The cVE199 molecule was revealed to have a specific binding reactivity against human VEGF-D, as well as a specific inhibitory activity against the binding of human VEGF-D to VEGFR-3. In addition, cVE199 was found to inhibit the biological activity of VEGF-D against lymphatic cells in vitro. Because we determined that a neuroblastoma cell line, SK-N-DZ, abundantly expressed VEGF-D, an in vivo efficacy study was performed using a xenograft model of SK-N-DZ. We found that cVE199 significantly decreased lymphatic metastasis of SK-N-DZ as well as lymphangiogenesis in primary lesions. Finally, we investigated VEGF-D expression in human neuroblastoma, finding that the molecule was expressed in 11 of 29 human neuroblastoma specimens (37.9%). In conclusion, we found that a novel anti-VEGF-D monoclonal antibody, cVE199, with specific reactivity against human VEGF-D, prevents lymphatic metastasis of neuroblastoma through the inhibition of lymphangiogenesis in an animal model. In addition, our results show that VEGF-D is expressed in some cases of human neuroblastomas, which suggests that cVE199 is a potential anti-metastasis therapeutic antibody in neuroblastoma treatment.
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http://dx.doi.org/10.1111/cas.12010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659268PMC
December 2012

Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis.

PLoS Pathog 2012 16;8(8):e1002860. Epub 2012 Aug 16.

Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.
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http://dx.doi.org/10.1371/journal.ppat.1002860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420934PMC
December 2012

An orally available, small-molecule interferon inhibits viral replication.

Sci Rep 2012 10;2:259. Epub 2012 Feb 10.

Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., Kamakura, Kanagawa, Japan.

Most acute hepatitis C virus (HCV) infections become chronic and some progress to liver cirrhosis or hepatocellular carcinoma. Standard therapy involves an interferon (IFN)-α-based regimen, and efficacy of therapy has been significantly improved by the development of protease inhibitors. However, several issues remain concerning the injectable form and the side effects of IFN. Here, we report an orally available, small-molecule type I IFN receptor agonist that directly transduces the IFN signal cascade and stimulates antiviral gene expression. Like type I IFN, the small-molecule compound induces IFN-stimulated gene (ISG) expression for antiviral activity in vitro and in vivo in mice, and the ISG induction mechanism is attributed to a direct interaction between the compound and IFN-α receptor 2, a key molecule of IFN-signaling on the cell surface. Our study highlights the importance of an orally active IFN-like agent, both as a therapy for antiviral infections and as a potential IFN substitute.
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http://dx.doi.org/10.1038/srep00259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277087PMC
April 2013

Angiogenesis inhibitors identified by cell-based high-throughput screening: synthesis, structure-activity relationships and biological evaluation of 3-[(E)-styryl]benzamides that specifically inhibit endothelial cell proliferation.

Bioorg Med Chem 2012 Feb 5;20(4):1442-60. Epub 2012 Jan 5.

Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.

Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) proliferation inhibitors from a cell-based high-throughput screening (HTS), we eliminated those compounds which showed cytotoxicity against HCT116 and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitory activity. Evaluations in human Calu-6 xenograft model delivered lead compound 1. Following extensive lead optimization and alteration of the scaffold we discovered 32f and 32g, which both inhibited the proliferation and tube formation of HUVEC without showing inhibitory activity against any of 25 kinases or cytotoxicity against either normal fibroblasts or 40 cancer cell lines. Upon oral administration, 32f and 32g had good pharmacokinetic profiles and potent antitumor activity and decreased microvessel density (MVD) in Calu-6 xenograft model. Combination therapy with a VEGFR inhibitor enhanced the in vivo efficacy. These results suggest that 32f and 32g may have potential for use in cancer treatment.
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http://dx.doi.org/10.1016/j.bmc.2011.12.058DOI Listing
February 2012

Preclinical antitumor activity of the novel heat shock protein 90 inhibitor CH5164840 against human epidermal growth factor receptor 2 (HER2)-overexpressing cancers.

Cancer Sci 2012 Feb 13;103(2):342-9. Epub 2011 Dec 13.

Pharmaceutical Research Department 2, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.

Heat shock protein 90 (Hsp90), a molecular chaperone that plays a significant role in the stability and maturation of client proteins, including oncogenic targets for cell transformation, proliferation, and survival, is an attractive target for cancer therapy. We identified the novel Hsp90 inhibitor, CH5164840, and investigated its induction of oncogenic client protein degradation, antiproliferative activity, and apoptosis against an NCI-N87 gastric cancer cell line and a BT-474 breast cancer cell line. Interestingly, CH5164840 demonstrated tumor selectivity both in vitro and in vivo, binding to tumor Hsp90 (which forms active multiple chaperone complexes) in vitro, and being distributed effectively to tumors in a mouse model, which, taken together, supports the decreased levels of phosphorylated Akt by CH5164840 that we observed in tumor tissues, but not in normal tissues. As well as being well tolerated, the oral administration of CH5164840 exhibited potent antitumor efficacy with regression in NCI-N87 and BT-474 tumor xenograft models. In addition, CH5164840 significantly enhanced antitumor efficacy against gastric and breast cancer models when combined with the human epidermal growth factor receptor 2 (HER2)-targeted agents, trastuzumab and lapatinib. These data demonstrate the potent antitumor efficacy of CH5164840 when administered alone, and its significant combination efficacy when combined with trastuzumab or lapatinib, supporting the clinical development of CH5164840 as an Hsp90 inhibitor for combination therapy with HER2-targeted agents against HER2-overexpressing tumors.
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http://dx.doi.org/10.1111/j.1349-7006.2011.02144.xDOI Listing
February 2012

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design.

Bioorg Med Chem Lett 2011 Oct 6;21(19):5778-83. Epub 2011 Aug 6.

Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.

Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.001DOI Listing
October 2011

Identification of a checkpoint modulator with synthetic lethality to p53 mutants.

Anticancer Drugs 2011 Nov;22(10):986-94

Pharmaceutical Research Department II, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.

The G(2) checkpoint is an indispensable pathway for cancers lacking p53 function, for delaying cell cycle progression, and for completing DNA repair. Therefore, disruption of this pathway is expected to offer selective therapy for these highly prevalent cancers. The aim of this study was to identify an inhibitor of the G(2) checkpoint including the ataxia-telangiectasia-mutated and Rad3-related checkpoint kinase 1 pathway that selectively suppresses the growth of p53-deficient cells. To obtain molecules with a novel mechanism of action, we constructed a high-throughput screening system that detected abrogation of the G(2) checkpoint in X-irradiated HT-29 cells. The screening resulted in identification of a guanidine analog, CBP-93872 that dose dependently inhibited the G(2) checkpoint induced by DNA damage. Interestingly, CBP-93872 directly suppressed the growth of p53-mutated cancer cell lines with wild-type CDKN2A by eliciting G(1) arrest, but not CDKN2A-deleted and/or wild-type p53 lines. CBP-93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1, but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays. These results suggest that a checkpoint modulator through suppression of Chk1 phosphorylation provides synthetic lethality to p53-deficient cells.
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http://dx.doi.org/10.1097/CAD.0b013e328349dd43DOI Listing
November 2011

Establishment of an immortalized human endometrial stromal cell line with functional responses to ovarian stimuli.

Reprod Biol Endocrinol 2011 Aug 1;9:104. Epub 2011 Aug 1.

Kamakura Research Laboratories, Chugai Pharmaceutical Co, Ltd, Kamakura, Kanagawa, Japan.

Studies on the mechanisms of decidualization and endometriosis are often hampered by lack of primary endometrial cells. To facilitate in vitro studies, we established a human endometrial stromal cell line, KC02-44D, immortalized with human telomerase reverse transcriptase. Upon exposure to ovarian stimuli, KC02-44D cells showed similar cytoskeletal marker or gene expression and biochemical phenotype to primary endometrial stromal cells. KC02-44D would be useful for studies of human endometrial function and its associated pathologies.
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http://dx.doi.org/10.1186/1477-7827-9-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160358PMC
August 2011

CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.

Cancer Cell 2011 May;19(5):679-90

Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
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http://dx.doi.org/10.1016/j.ccr.2011.04.004DOI Listing
May 2011

The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations.

Clin Cancer Res 2011 May 10;17(10):3272-81. Epub 2011 May 10.

Pharmaceutical Research Department 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co Ltd, Kamakura, Kanagawa, Japan.

Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.

Experimental Design: Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.

Results: CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.

Conclusions: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2882DOI Listing
May 2011

Cutaneous lymphoplasmacytic lymphoma with systemic metastasis in a cat.

J Vet Med Sci 2011 Sep 6;73(9):1221-4. Epub 2011 May 6.

North Lab, 2–10 Atsubetsu-Nishi 2–4 Atsubetsu-ku, Sapporo 004–0062, Japan.

A lymphoplasmacytic lymphoma was diagnosed in a 12- year-old domestic cat that had a primary cutaneous mass involving the stomach, liver, kidneys, heart, abdominal wall, diaphragm, bone marrow and several lymph nodes. Histopathologically, the most characteristic feature of this tumor was the heterogeneity of cell components, such as small lymphocytes, well-differentiated plasma cells and plasmacytoid transformed lymphocytes. Amyloid was deposited in the skin, stomach, and several lymph nodes. Immunohistochemically, neoplastic small lymphocytes were positive for CD20, and well-differentiated plasma cells and plasmacytoid transformed lymphocytes were positive for λ-Ig light chains and MUM1/IRF-4. These results emphasize the importance of lymphoplasmacytic lymphoma as a differential diagnosis of extramedullary cutaneous plasmacytoma in cats.
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http://dx.doi.org/10.1292/jvms.10-0451DOI Listing
September 2011

Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799.

Bioorg Med Chem Lett 2011 Mar 22;21(6):1767-72. Epub 2011 Jan 22.

Research Division, Chugai Pharmaceutical Co., Ltd , Kamakura, Kanagawa, Japan.

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase and a promising therapeutic target for cancer. Using structure-based drug design (SBDD), we have identified novel PI3K inhibitors with a dihydropyrrolopyrimidine skeleton. Metabolic stability of the first lead series was drastically improved by replacing phenol with aminopyrimidine moiety. CH5132799, a novel class I PI3K inhibitor, exhibited a strong inhibitory activity especially against PI3Kα (IC(50)=0.014 μM). In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice.
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http://dx.doi.org/10.1016/j.bmcl.2011.01.065DOI Listing
March 2011
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