Discovery of Novel 2,4,5-Trisubstituted Pyrimidine Derivatives as Potent and Selective FGFR Inhibitors against Gatekeeper Mutants for the Treatment of NSCLC

Article

Author: Zhang, Jianxia ; Wang, Kun ; Chen, Chaoyue ; Wang, Peipei ; Cao, Di ; Wang, Yi ; Yan, Hao ; Wang, Mengying ; Li, Xiaokun ; Li, Bin ; Wang, Dalong ; Zheng, Xiaohui ; Zheng, Jiahao ; Liu, Zhiguo

Fibroblast growth factor receptors (FGFRs) play a critical role in the regulation of cancer cell proliferation, differentiation, and migration. However, the development of acquired resistance to FGFR inhibitors remains a major challenge in treating non-small cell lung cancer (NSCLC), particularly due to mutations at the gatekeeper residue. In this study, we report the discovery of a series of irreversible FGFR inhibitors targeting gatekeeper mutations in FGFR1-3, utilizing a 2,4,5-trisubstituted pyrimidine scaffold. Through rational design, structure-activity relationship optimization, and pharmacokinetic evaluation, compound ng 12l emerged as a promising candidate. It demonstrated potent inhibition of FGFR1-3 gatekeeper mutations in vitro along with favorable pharmacokinetic properties. The efficacy of 12l in targeting FGFR1 gatekeeper mutations was confirmed in assays using L6-FGFR1^V561M/F cells. Furthermore, in xenograft models using both H1581 and L6-FGFR1^V561M cells, 12l exhibited robust anti-tumor activity with minimal toxicity. These findings position 12l as a promising therapeutic agent for overcoming gatekeeper-mediated resistance in NSCLC.

27 Feb 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine

Q1 · MEDICINE

Article

Author: Du, Guangyan ; Henning, Nathaniel J. ; Gray, Nathanael S. ; Aguirre, Andrew J. ; Yang, Annan ; Ficarro, Scott B. ; Marto, Jarrod A. ; Gurbani, Deepak ; Che, Jianwei ; Zhang, Tinghu ; Westover, Kenneth D. ; Sorger, Peter K. ; Jiang, Jie ; Rao, Suman

SRC is a major regulator of many signaling pathways and contributes to cancer development. However, development of a selective SRC inhibitor has been challenging, and FDA-approved SRC inhibitors, dasatinib and bosutinib, are multitargeted kinase inhibitors. Here, we describe our efforts to develop a selective SRC covalent inhibitor by targeting cysteine 277 on the P-loop of SRC. Using a promiscuous covalent kinase inhibitor (CKI) SM1-71 as a starting point, we developed covalent inhibitor 15a, which discriminates SRC from other covalent targets of SM1-71 including TAK1 and FGFR1. As an irreversible covalent inhibitor, compound 15a exhibited sustained inhibition of SRC signaling both in vitro and in vivo. Moreover, 15a exhibited potent antiproliferative effects in nonsmall cell lung cancer cell lines harboring SRC activation, thus providing evidence that this approach may be promising for further drug development efforts.

01 Jun 2019·Cell Chemical BiologyQ1 · BIOLOGY

Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Q1 · BIOLOGY

Article

Author: Westover, Kenneth D ; Marto, Jarrod A ; Sim, Taebo ; Rao, Suman ; Sorger, Peter K ; Knapp, Stefan ; Schröder, Martin ; Ficarro, Scott B ; Gray, Nathanael S ; Kim, Nam Doo ; Du, Guangyan ; Gurbani, Deepak ; Everley, Robert A ; Gondi, Sudershan ; Tan, Li ; Berberich, Matthew J ; Chaikuad, Apirat ; Browne, Christopher M

Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development.

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	United States	Dana-Farber Cancer Institute, Inc.	01 Feb 2017
Neoplasms	Preclinical	United States	Dana-Farber Cancer Institute, Inc.	01 Feb 2017

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