Publications by authors named "Xiaobao Yang"

33 Publications

Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation.

Eur J Med Chem 2021 Nov 25;223:113645. Epub 2021 Jun 25.

Shanghai Institute for Advanced Immunochemical Studies, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address:

Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL leukemia.
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http://dx.doi.org/10.1016/j.ejmech.2021.113645DOI Listing
November 2021

Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile.

J Med Chem 2021 07 17;64(13):9152-9165. Epub 2021 Jun 17.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00373DOI Listing
July 2021

CXCL8 Associated Dendritic Cell Activation Marker Expression and Recruitment as Indicators of Favorable Outcomes in Colorectal Cancer.

Front Immunol 2021 7;12:667177. Epub 2021 May 7.

Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Accumulating evidence suggests that tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serve as promising therapeutic targets. CXCL8 (IL-8) may also be a potential therapeutic target in cancer. CXCL8 is a potent chemotactic factor for neutrophils, myeloid-derived suppressor cells (MDSCs) and monocytes, which are considered immunosuppressive components in cancer-bearing hosts. Here, we identified the TME-related gene CXCL8 in a high-ImmuneScore population that contributed to better survival in colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. An integrated gene profile and functional analysis of TIC proportions revealed that the dendritic cell (DC) activation markers CD80, CD83, and CD86 were positively correlated with CXCL8 expression, suggesting that CXCL8 may be functional as antitumor immune response status in the TME. The gene signature was further validated in independent GSE14333 and GSE38832 cohorts from the Gene Expression Omnibus (GEO). To test the differential contributions of immune and tumor components to progression, three CRC cell lines, CT26, MC38 and HCT116, were used. results suggested no significant growth or survival changes following treatment with an inhibitor of the CXCL8 receptor (CXCR1/2) such as reparixin or danirixin. treatment with danirixin (antagonists of CXCR2) promoted tumor progression in animal models established with CT26 cells. CXCR2 antagonism may function an immune component, with CXCR2 antagonist treatment in mice resulting in reduced activated DCs and correlating with decreased Interferon gamma (IFN-γ) or Granzyme B expressed CD8 T cells. Furthermore, CXCL8 induced DC migration in transwell migration assays. Taken together, our data suggested that targeting the CXCL8-CXCR2 axis might impede DC activation or recruitment, and this axis could be considered a favorable factor rather than a target for critical antitumor effects on CRC.
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http://dx.doi.org/10.3389/fimmu.2021.667177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138166PMC
May 2021

Long non-coding RNA MFAT1 promotes skeletal muscle fibrosis by modulating the miR-135a-5p-Tgfbr2/Smad4 axis as a ceRNA.

J Cell Mol Med 2021 05 9;25(9):4420-4433. Epub 2021 Apr 9.

Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Fibrosis after skeletal muscle injury is common in sports and can cause irreversible damage to the biomechanical properties of skeletal muscle. Long non-coding RNAs (lncRNAs) have been validated to act as important modulators in the fibrosis of various organs. Here, we reported a novel lncRNA (the skeletal muscle fibrosis-associated transcript 1, lnc-MFAT1), which was highly expressed in skeletal muscle fibrosis. We demonstrate that lnc-MFAT1 knockdown can reduce TGFβ-induced fibrosis in vitro and attenuate skeletal muscle fibrosis after acute contusion in mice. Further study showed that lnc-MFAT1 acted as a competitive endogenous RNA of miR-135a-5p. Besides, the miR-135a-5p inhibition obviously promoted TGFβ-induced fibrosis in vitro via enhancing its target genes Tgfbr2/Smad4. Moreover, we discovered that lnc-MFAT1 regulates Tgfbr2/Smad4 expression by sponging miR-135a-5p to exert competing endogenous RNA function, resulting in TGFβ pathway activation. In conclusion, our study identified a crucial role of lnc-MFAT1-miR-135a-Tgfbr2/Smad4 axis in skeletal muscle fibrosis, providing a promising treatment option against skeletal muscle fibrosis.
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http://dx.doi.org/10.1111/jcmm.16508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093971PMC
May 2021

Effective degradation of EGFR mutant proteins by CRBN-based PROTACs through both proteosome and autophagy/lysosome degradation systems.

Eur J Med Chem 2021 Jun 7;218:113328. Epub 2021 Mar 7.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address:

Targeted therapy of treating patients with specific tyrosine kinase inhibitors (TKIs) is currently the standard care for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. However, the inevitably developed drug resistance in patients to EGFR TKIs is the biggest obstacle for cancer targeted therapy. About 60% of drug resistance to the 1st generation of EGFR TKIs was resulted from an acquired T790M mutation in the kinase domain of EGFR protein. Proteolysis targeting chimera (PROTAC) is a lately-developed technology to target point of interest proteins for degradation. Because EGFR-mutant lung cancers are highly dependent on EGFR proteins, designing specific PROTAC molecules to degrade EGFR proteins from cancer cells provides a very promising strategy to treat such patients and eradicate drug resistance. Currently, there is no cereblon (CRBN)-based PROTAC reported able to degrade T790M-containing EGFR resistant proteins. In this study, we synthesized two novel CRBN-based EGFR PROTACs, SIAIS125 and SIAIS126, based on EGFR inhibitor canertinib and cereblon ligand pomalidomide. These two degraders displayed potent and selective antitumor activities in EGFR TKI resistant lung cancer cells. Firstly, they could selectively degrade EGFR resistant proteins in H1975 cells at the concentration of 30-50 nM, and EGFR proteins in PC9 cells. But they did not degrade EGFR mutant proteins in PC9Brca1 cells or wild type EGFR in A549 lung cancer cells. They could also selectively inhibit the growth of EGFR mutant lung cancer cells but not that of normal cells or A549 cells. Secondly, the degradation of EGFR proteins was long lasting up to 72 h. Thirdly, these degraders displayed better inhibition of EGFR phosphorylation in H1975 cells and PC9Brca1 cells comparing to canertinib. Finally, these degraders could also induce significant apoptosis and cell cycles arrest in H1975 cells. Pre-incubation with canertinib, pomalidomide or ubiquitination inhibitor MLN4924 totally blocked EGFR degradation by PROTACs. Mechanistic studies showed that PROTAC could induce autophagy in lung cancer cells. PROTAC-induced EGFR degradation acted through both ubiquitin/proteosome system and ubiquitin/autophagy/lysosome system. Elevating autophagy activities enhanced EGFR degradation and cell apoptosis induced by PROTACs. Our research not only offered a novel PROTAC tool to target EGFR TKI drug resistance in lung cancer, but also firstly demonstrated that the involvement of autophagy/lysosome system in PROTAC- mediated target protein degradation.
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http://dx.doi.org/10.1016/j.ejmech.2021.113328DOI Listing
June 2021

Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib.

Eur J Med Chem 2021 May 11;217:113335. Epub 2021 Mar 11.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address:

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.
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http://dx.doi.org/10.1016/j.ejmech.2021.113335DOI Listing
May 2021

Prophylactic subcutaneous drainage reduces post-operative incisional infections in colorectal surgeries: a meta-analysis of randomized controlled trials.

Int J Colorectal Dis 2021 Aug 15;36(8):1633-1642. Epub 2021 Mar 15.

Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion and Metastasis Research and National Clinical Research Center for Digestive Diseases, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.

Background: Due to lack of high-level evidences, prophylactic subcutaneous drainage has so far not been recommended in relevant guidelines as a countermeasure against incisional infections. This meta-analysis aims to clarify the efficacy of subcutaneous drainage in reducing incisional infections in colorectal surgeries.

Methods: Cochrane Library, Embase, and PubMed were searched for randomized controlled trials comparing the incidence rate of incisional infections between patients receiving prophylactic subcutaneous drainage (interventions) and those not receiving (controls) after digestive surgeries. Results from included RCTs were pooled multiple times according to different surgical types. Heterogeneity, publication bias, and certainty of evidences were estimated.

Results: Eight randomized controlled trials were included. Three RCTs each included patients receiving all sorts of digestive surgeries (gastrointestinal, hepatobiliary, and pancreatic); pooled incisional infection rates between the drainage group and the control group were not significantly different (RR = 0.76, 95%CI: 0.48-1.21, p = 0.25). Four RCTs included patients receiving colorectal surgeries; pooled incisional infection rate in the drainage group was significantly lower than that in the control group (RR = 0.34, 95%CI: 0.19-0.61, p = 0.0004). Four RCTs included patients receiving upper GI and/or HBP surgeries; pooled incisional infection rates in the drainage group and the non-drainage group were not significantly different (RR = 0.85, 95%CI: 0.54-1.34, p = 0.49).

Conclusions: Prophylactic subcutaneous drainage significantly reduces post-operative incisional infections in colorectal surgeries but was not efficacious in digestive surgeries in general.
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http://dx.doi.org/10.1007/s00384-021-03908-8DOI Listing
August 2021

Construction of an IMiD-based azide library as a kit for PROTAC research.

Org Biomol Chem 2021 01;19(1):166-170

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.

As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment. Here we report the efficient construction of an IMiD-based azide library via a quick one-step conversion of the existing IMiD-based amine library. This new azide library can act as a kit to endow PROTAC libraries with triazole moieties for various POIs through a highly effective 'click reaction' and then help to rapidly screen out lead degraders that are valuable for drug development. Its power in fleetly identifying potent degraders has been verified on two oncogenic proteins, BCR-ABL and BET, the degraders of which showed comparable potency to or even higher potency than the reported PROTACs in degrading target proteins and effectively inhibiting cancer cell proliferation.
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http://dx.doi.org/10.1039/d0ob02120bDOI Listing
January 2021

Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.

Cell 2020 07 22;182(2):417-428.e13. Epub 2020 May 22.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing, China. Electronic address:

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
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http://dx.doi.org/10.1016/j.cell.2020.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242921PMC
July 2020

Enhanced Transformation of Cr(VI) by Heterocyclic-N within Nitrogen-Doped Biochar: Impact of Surface Modulatory Persistent Free Radicals (PFRs).

Environ Sci Technol 2020 07 17;54(13):8123-8132. Epub 2020 Jun 17.

School of Environmental Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.

Redox processes mediated by biochar(BC) enhanced the transformation of Cr(VI), which is largely dependent on the presence of PFRs as electron donors. Natural or artificial dopants in BC's could regulate inherent carbon configuration and PFRs. Until recently, the modulation of PFRs and transformation of Cr(VI) in BC by nonmetal-heterocyclic dopants was barely studied. In this study, changes in PFRs introduced by various nitrogen-dopants within BC are presented and the capacity for Cr(VI) transformation without light was investigated. It was found N-dopants were effectively embedded in carbon lattices through activated-Maillard reaction thus altering their charge and PFRs. Transformation of Cr(VI) in N doped biochar relied on mediated direct reduction by surface modulatory PFRs. The kinetic rate of transformation of Cr(VI) was increased 1.4-5 fold in N-BCs compared to nondoped BCs. Theortical calculation suggested a deficiency in surface electrons induced Lewis acid-base bonding which could acted as a bridge for electron transfer. Results of PCA and orbital energy indicated a colinear relationship between PFRs and pyrrolic N, as well as its dual-mode transformation of Cr(VI). This study provides an improved understanding of how N-doped BC contributes to the evolution of PFRs and their corresponding impacts on the transformation of Cr(VI) in environments.
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http://dx.doi.org/10.1021/acs.est.0c02713DOI Listing
July 2020

Adsorption-Free Growth of Ultra-Thin Molybdenum Membranes with a Low-Symmetry Rectangular Lattice Structure.

Small 2020 Jul 2;16(26):e2001325. Epub 2020 Jun 2.

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China.

Although low-symmetry lattice structure of 2D transition metals is highly anticipated for both fundamental research and potentially distinctive application, it still has not been experimentally realized, which greatly hinders the exploration of the unique properties. Here, ultra-thin body-centered-cubic (bcc) phase molybdenum (Mo) membranes are successfully synthesized with a low-symmetry rectangular (110) crystal face via an adsorption-free reaction. Through experimental and density functional theory studies, no foreign atoms being adsorbed is shown to be a key factor for the successful preparation of the bcc phase 2D transition metal with (110) faces. The realization of 2D Mo(110) with a low-symmetric rectangular lattice structure extends the scope of 2D structures and is also beneficial for the exploration and development of low-symmetry rectangular lattice-structured materials with unique properties.
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http://dx.doi.org/10.1002/smll.202001325DOI Listing
July 2020

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur.

Nat Struct Mol Biol 2020 06 7;27(6):529-532. Epub 2020 May 7.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (M). Here, the X-ray crystal structure of M in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.
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http://dx.doi.org/10.1038/s41594-020-0440-6DOI Listing
June 2020

Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.

Eur J Med Chem 2020 May 29;193:112190. Epub 2020 Feb 29.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address:

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.
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http://dx.doi.org/10.1016/j.ejmech.2020.112190DOI Listing
May 2020

Discovery of a first-in-class EZH2 selective degrader.

Nat Chem Biol 2020 02 9;16(2):214-222. Epub 2019 Dec 9.

Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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http://dx.doi.org/10.1038/s41589-019-0421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609PMC
February 2020

Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.

J Med Chem 2019 10 2;62(20):9281-9298. Epub 2019 Oct 2.

CAS Key Laboratory of Synthetic Chemistry of Natural Substances , Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Road , Shanghai 200032 , China.

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL leukemia.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01264DOI Listing
October 2019

Chemoselective Synthesis of Lenalidomide-Based PROTAC Library Using Alkylation Reaction.

Org Lett 2019 05 8;21(10):3838-3841. Epub 2019 May 8.

CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry , Chinese Academy of Sciences , 345 Lingling Road , Shanghai 200032 , China.

An organic base-promoted chemoselective alkylation of lenalidomide with different halides was developed, which offers a novel approach to a highly functionalized lenalidomide-based PROTAC library under mild reaction conditions. DIPEA was found to act as an efficient base to trigger facile generation of arylamine alkylation products compared with inorganic bases. This library was successfully applied to BET PROTAC, which not only degraded BET protein but also effectively inhibited cancer cell proliferation.
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http://dx.doi.org/10.1021/acs.orglett.9b01326DOI Listing
May 2019

Factors influencing traffic accident frequencies on urban roads: A spatial panel time-fixed effects error model.

PLoS One 2019 4;14(4):e0214539. Epub 2019 Apr 4.

Key Laboratory of Road and Traffic Engineering of Ministry of Education, Tongji University, Shanghai, China.

China's rapid urbanization and high traffic accident frequency have received many researchers' attention. It is important to reveal how urban infrastructures and other risk factors affects the traffic accident frequency. A growing amount of research has examined the local risk factors impact on traffic accident frequency at certain time. Some studies considered these spatial influences but overlooked the temporal correlation/heterogeneity of traffic accidents and related risk factors. This study explores risk factors' influence on urban traffic accidents frequency while considering both the spatial and temporal correlation/heterogeneity of traffic accidents. The study area is split into 100 equally sized rectangle traffic analysis zones (TAZs), and the urban traffic accident frequency and attributes in each TAZ are extracted. The linear regression model, spatial lag model (SLM), spatial error model (SEM) and time-fixed effects error model (T-FEEM) are established and compared respectively. The proposed methodologies are illustrated using ten-month traffic accident data from the urban area of Guiyang City, China. The results reveal that the time-fixed effects error model, which considers both spatial and temporal correlation/heterogeneity of traffic accidents, is superior to other models. More traffic accidents will happen in those TAZs that have more hospitals or schools. Moreover, hospitals have a greater influence on traffic accidents than schools. Because of the location in the margin of the city, those TAZs that have passenger stations have more traffic accidents. This study provides policy makers with more detailed characterization about the impact of related risk factors on traffic accident frequencies, and it is suggested that not only the spatial correlation/heterogeneity but also the temporal correlation/heterogeneity should be taken into account in guiding traffic accident control of urban area.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448912PMC
December 2019

Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target.

Cell 2019 01;176(3):636-648.e13

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300353, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; Laboratory of Structural Biology, Tsinghua University, Beijing, 100084, China. Electronic address:

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.
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http://dx.doi.org/10.1016/j.cell.2019.01.003DOI Listing
January 2019

Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK).

Eur J Med Chem 2018 May 27;151:304-314. Epub 2018 Mar 27.

Center for Chemical Biology and Drug Discovery, Department of Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY10029, United States. Electronic address:

Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924614PMC
May 2018

Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).

J Med Chem 2018 02 5;61(3):1204-1217. Epub 2018 Jan 5.

Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC values: ∼10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808361PMC
February 2018

Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.

Proc Natl Acad Sci U S A 2016 12 1;113(50):E8178-E8186. Epub 2016 Dec 1.

Department of Cell Biology, Duke University Medical Center, Durham, NC 27710;

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.
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http://dx.doi.org/10.1073/pnas.1614347113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167191PMC
December 2016

Structure-Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors.

J Med Chem 2016 08 11;59(16):7617-33. Epub 2016 Aug 11.

Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , One Gustave L. Levy Place, Room 16-20B, Box 1677, New York, New York 10029, United States.

EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003625PMC
August 2016

An accelerated failure time model for investigating pedestrian crossing behavior and waiting times at signalized intersections.

Accid Anal Prev 2015 Sep 11;82:154-62. Epub 2015 Jun 11.

MOE Key Laboratory for Urban Transportation Complex Systems Theory and Technology, Beijing Jiaotong University, Beijing 100044, China.

The waiting process is crucial to pedestrians in the street-crossing behavior. Once pedestrians terminate their waiting behavior during the red light period, they would cross against the red light and put themselves in danger. A joint hazard-based duration model is developed to investigate the effect of various covariates on pedestrian crossing behavior and to estimate pedestrian waiting times at signalized intersections. A total of 1181 pedestrians approaching the intersections during red light periods were observed in Beijing, China. Pedestrian crossing behaviors are classified into immediate crossing behavior and waiting behavior. The probability and effect of various covariates for pedestrians' immediate crossing behavior are identified by a logit model. Four accelerated failure time duration models based on the exponential, Weibull, lognormal and log-logistic distributions are proposed to examine the significant risk factors affecting duration times for pedestrians' waiting behavior. A joint duration model is developed to estimate pedestrian waiting times. Moreover, unobserved heterogeneity is considered in the proposed model. The results indicate that the Weibull AFT model with shared frailty is appropriate for modelling pedestrian waiting durations. Failure to account for heterogeneity would significantly underestimate the effects of covariates on waiting duration times. The proposed model provides a better understanding of pedestrian crossing behavior and more accurate estimation of pedestrian waiting times. It may be applicable in traffic system analysis in developing countries with high flow of mixed traffic.
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http://dx.doi.org/10.1016/j.aap.2015.04.036DOI Listing
September 2015

A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3).

Angew Chem Int Ed Engl 2015 Apr 27;54(17):5166-70. Epub 2015 Feb 27.

Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and System Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 (USA).

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell-active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31±2 nM, KD =53±2 nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.
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http://dx.doi.org/10.1002/anie.201412154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400258PMC
April 2015

The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs.

ACS Chem Neurosci 2015 Mar 27;6(3):476-84. Epub 2015 Jan 27.

†Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.
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http://dx.doi.org/10.1021/cn500325vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368042PMC
March 2015

A hazard-based duration model for analyzing crossing behavior of cyclists and electric bike riders at signalized intersections.

Accid Anal Prev 2015 Jan 22;74:33-41. Epub 2014 Oct 22.

MOE Key Laboratory for Urban Transportation Complex Systems Theory and Technology, Beijing Jiaotong University, Beijing 100044, China.

This paper presents a hazard-based duration approach to investigate riders' waiting times, violation hazards, associated risk factors, and their differences between cyclists and electric bike riders at signalized intersections. A total of 2322 two-wheeled riders approaching the intersections during red light periods were observed in Beijing, China. The data were classified into censored and uncensored data to distinguish between safe crossing and red-light running behavior. The results indicated that the red-light crossing behavior of most riders was dependent on waiting time. They were inclined to terminate waiting behavior and run against the traffic light with the increase of waiting duration. Over half of the observed riders cannot endure 49s or longer. 25% of the riders can endure 97s or longer. Rider type, gender, waiting position, conformity tendency and crossing traffic volume were identified to have significant effects on riders' waiting times and violation hazards. Electric bike riders were found to be more sensitive to the external risk factors such as other riders' crossing behavior and crossing traffic volume than cyclists. Moreover, unobserved heterogeneity was examined in the proposed models. The finding of this paper can explain when and why cyclists and electric bike riders run against the red light at intersections. The results of this paper are useful for traffic design and management agencies to implement strategies to enhance the safety of riders.
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http://dx.doi.org/10.1016/j.aap.2014.10.014DOI Listing
January 2015

Efficient total synthesis of marine alkaloid (-)-nakadomarin A.

Chemistry 2011 Nov 29;17(45):12569-72. Epub 2011 Sep 29.

Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, P.R. China.

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http://dx.doi.org/10.1002/chem.201102101DOI Listing
November 2011

Modeling pedestrian violation behavior at signalized crosswalks in China: a hazards-based duration approach.

Traffic Inj Prev 2011 Feb;12(1):96-103

Institute of System Science, School of Traffic and Transportation, Beijing Jiaotong University, Beijing, China.

Objective: Pedestrian violation is a major cause of traffic accidents involving pedestrians. The research objectives were to investigate the relationship between waiting duration and pedestrian violation and to provide a qualitative and quantitative analysis of the effects of human factors and external environmental factors on street-crossing behavior.

Methods: Pedestrians' street-crossing behavior was examined by modeling the waiting duration at signalized crosswalk. Pedestrian waiting duration was collected by video cameras and it was assigned as censored and uncensored data to distinguish between normal crossing and violating crossing. A nonparametric baseline duration model was introduced, and variables revealing personal characteristics, traffic conditions, and trip features were defined as covariates to describe the effects of internal and external factors.

Results: Pedestrians' crossing behaviors represented positive duration dependence that the longer the waiting time elapsed the more likely pedestrians would end the wait soon. The violation inclination of most pedestrians increased with the increasing waiting duration, but about 10 percent of pedestrians were at high risk of violation to cross the street. About half of pedestrians would still obey the traffic rules even after waiting for 50 s by the street. Human factors and the external environment played an important role in street-crossing behavior, especially for factors that involved pedestrians' subjective willingness.

Conclusions: The street-crossing behavior of pedestrians was time dependent. Pedestrians behave differently under the effects of various factors. Pedestrian safety interventions that aim at reducing pedestrian injuries may need to consider these effects. The pedestrians' behavioral modifications, such as enhancing the safety awareness, might be the most efficient means to reducing the likelihood of pedestrian violation, though environmental modifications also worked well in improving pedestrian safety.
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http://dx.doi.org/10.1080/15389588.2010.518652DOI Listing
February 2011

Water-soluble fluorescent carbon quantum dots and photocatalyst design.

Angew Chem Int Ed Engl 2010 Jun;49(26):4430-4

Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou, Jiangsu, P.R. China.

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http://dx.doi.org/10.1002/anie.200906154DOI Listing
June 2010

Design, multicomponent synthesis, and bioactivities of novel neonicotinoid analogues with 1,4-dihydropyridine scaffold.

J Agric Food Chem 2010 Mar;58(5):2741-5

Shanghai Key Laboratory of Chemistry Biology, Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, Shanghai, China 200237.

Novel neonicotinoid analogues bearing a 1,4-dihydropridine scaffold were designed and synthesized by multicomponent reactions (MCRs) to enhance pi-pi stacking. The synthesized compounds were identified by (1)H NMR, (13)C NMR, high-resolution mass spectroscopy, and elemental analysis. Bioassay tests showed that some of them exhibited high insecticidal activities against pea aphid ( Aphis craccivora ).
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http://dx.doi.org/10.1021/jf902034zDOI Listing
March 2010
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