Publications by authors named "Lingtian Zhang"

9 Publications

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Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.

Eur J Med Chem 2021 Apr 9;216:113265. Epub 2021 Feb 9.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.
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http://dx.doi.org/10.1016/j.ejmech.2021.113265DOI Listing
April 2021

Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.

Eur J Med Chem 2020 Nov 6;206:112691. Epub 2020 Aug 6.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address:

Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
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http://dx.doi.org/10.1016/j.ejmech.2020.112691DOI Listing
November 2020

Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression.

Eur J Med Chem 2020 Oct 12;203:112589. Epub 2020 Jul 12.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Electronic address:

Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
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http://dx.doi.org/10.1016/j.ejmech.2020.112589DOI Listing
October 2020

Screening the key genes of hair follicle growth cycle in Inner Mongolian Cashmere goat based on RNA sequencing.

Arch Anim Breed 2020 26;63(1):155-164. Epub 2020 May 26.

College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia Autonomous Region, 010018, China.

Inner Mongolian Cashmere goat is an excellent local breed selected for the dual-purpose of cashmere and meat. There are three lines of Inner Mongolian Cashmere goat: Erlangshan, Alashan and Aerbasi. Cashmere is a kind of precious textile raw material with a high price. Cashmere is derived from secondary hair follicle (SHF), while hair is derived from primary hair follicle (PHF). The growth cycle of SHF of cashmere goat is 1 year, and it can be divided into three different stages: anagen, catagen and telogen. In this study, we tried to find some important influence factors of SHF growth cycle in skin tissue from Inner Mongolian Cashmere goats by RNA sequencing (RNA-Seq). Three female Aerbasi Inner Mongolian Cashmere goats (2 years old) were used as experimental samples in this study. Skin samples were collected in September (anagen), December (catagen) and March (telogen) at dorsal side from cashmere goats. Results showed that over 511 396 044 raw reads and 487 729 890 clean reads were obtained from sequence data. In total, 51 different expression genes (DEGs) including 29 downregulated genes and 22 upregulated genes were enriched in anagen-catagen comparing group. The 443 DEGs contained 117 downregulated genes and 326 upregulated genes that were enriched in catagen-telogen comparing group. In telogen-anagen comparing group, 779 DEGs were enriched including 582 downregulated genes and 197 upregulated genes. The result of gene ontology (GO) annotation showed that DEGs are in different growth cycle periods, and enriched GO items are mostly related to the transformation of cell and protein. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment result indicated that metabolic process has a great impact on SHF growth cycle. Based on the results of a comprehensive analysis of differentially expressed genes, GO enrichment and KEGG enrichment, we found that , and had an effect on the hair follicle growth cycle. The results of this study may provide a theoretical basis for further research on the growth and development of SHF in Inner Mongolian Cashmere goats.
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http://dx.doi.org/10.5194/aab-63-155-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256851PMC
May 2020

Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology.

J Med Chem 2020 05 28;63(9):4506-4516. Epub 2020 Apr 28.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy.

RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed a selective inhibitory profile and an inhibitory concentration 50 (IC) of <0.003 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901654PMC
May 2020

Catalyst free, C-3 functionalization of imidazo[1,2-a]pyridines to rapidly access new chemical space for drug discovery efforts.

Chem Commun (Camb) 2018 Nov;54(92):12954-12957

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.

Multicomponent reactions (MCRs) are robust tools for the rapid synthesis of complex, small molecule libraries for use in drug discovery and development. By utilizing MCR chemistry, we developed a protocol to functionalize the C-3 position of imidazo[1,2-a]pyridine through a three component, decarboxylation reaction involving imidazo[1,2-a]pyridine, glyoxalic acid, and boronic acid.
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http://dx.doi.org/10.1039/c8cc07063fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284400PMC
November 2018

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

Sci Rep 2018 02 27;8(1):3722. Epub 2018 Feb 27.

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.
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http://dx.doi.org/10.1038/s41598-018-21839-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829162PMC
February 2018

Sulfation of benzyl alcohol by the human cytosolic sulfotransferases (SULTs): a systematic analysis.

J Appl Toxicol 2016 09 11;36(9):1090-4. Epub 2015 Dec 11.

Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH, 43614, USA.

The aim of the present study was to identify human cytosolic sulfotransferases (SULTs) that are capable of sulfating benzyl alcohol and to examine whether benzyl alcohol sulfation may occur in cultured human cells as well as in human organ homogenates. A systematic analysis revealed that of the 13 known human SULTs, SULT1A1 SULT1A2, SULTA3, and SULT1B1 are capable of mediating the sulfation of benzyl alcohol. The kinetic parameters of SULT1A1 that showed the strongest benzyl alcohol-sulfating activity were determined. HepG2 human hepatoma cells were used to demonstrate the generation and release of sulfated benzyl alcohol under the metabolic settings. Moreover, the cytosol or S9 fractions of human liver, lung, kidney and small intestine were examined to verify the presence of benzyl alcohol sulfating activity in vivo. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jat.3268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903095PMC
September 2016

Sulfation of afimoxifene, endoxifen, raloxifene, and fulvestrant by the human cytosolic sulfotransferases (SULTs): A systematic analysis.

J Pharmacol Sci 2015 Jul 25;128(3):144-9. Epub 2015 Jun 25.

Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH, 43614, USA. Electronic address:

Previous studies demonstrated that sulfate conjugation is involved in the metabolism of three commonly used breast cancer drugs, tamoxifen, raloxifene and fulvestrant. The current study was designed to systematically identify the human cytosolic sulfotransferases (SULTs) that are capable of sulfating raloxifene, fulvestrant, and two active metabolites of tamoxifen, afimoxifene and endoxifen. A systematic analysis using 13 known human SULTs revealed SULT1A1 and SULT1C4 as the major SULTs responsible for the sulfation of afimoxifene, endoxifen, raloxifene and fulvestrant. Kinetic parameters of these two human SULTs in catalyzing the sulfation of these drug compounds were determined. Sulfation of afimoxifene, endoxifen, raloxifene and fulvestrant under metabolic conditions was examined using HepG2 human hepatoma cells and MCF-7 breast cancer cells. Moreover, human intestine, kidney, liver, and lung cytosols were examined to verify the presence of afimoxifene/endoxifen/raloxifene/fulvestrant-sulfating activity.
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http://dx.doi.org/10.1016/j.jphs.2015.06.004DOI Listing
July 2015