2. Academic Validation
  3. Discovery and Optimization of a Novel 2 H-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor

Discovery and Optimization of a Novel 2 H-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor

  • J Med Chem. 2021 Jul 8;64(13):9078-9099. doi: 10.1021/acs.jmedchem.1c00174.
Yujiao Wei 1,  Yanting Tang 1,  Yunyun Zhou 1,  Yuyu Yang 1,  Yetong Cui 1,  Xuan Wang 1,  Yubo Wang 1,  Yulin Liu 1,  Ning Liu 1,  Qianqian Wang 1,  Chong Li 1,  Hao Ruan 1,  Honggang Zhou 1,  Mingming Wei 1,  Guang Yang 1,  Cheng Yang 1
Affiliations

Affiliation

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
PMID: 34129329 DOI: 10.1021/acs.jmedchem.1c00174
Abstract

Fibroblast Growth Factor receptors (FGFRs) have become promising therapeutic targets in various types of cancers. In fact, several selective irreversible inhibitors capable of covalently reacting with the conserved cysteine of FGFRs are currently being evaluated in clinical trials. In this article, we optimized and discovered a novel lead compound 36 with remarkable inhibitory effects against FGFR (1-3), which is a derivative of 2H-pyrazolo[3,4-d]pyrimidine. The irreversible binding to FGFRs was characterized by LC-MS. This compound has been shown to exhibit significant anti-proliferation effects against NCI-H1581 and SNU-16 Cancer cell lines both in vitro and in vivo. Compound 36 has also demonstrated a low toxicity profile and adequate pharmacokinetic properties and is currently under validation as a potential drug candidate.

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