Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation

Abstract

Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine scaffold. Rational design, optimization, and pharmacokinetic screening provided representative compound 19 with potent FGFR inhibition in vitro, high bioavailability, and an acceptable half-life. GK mutation tolerance was supported by assays against FGFR4V550L and Ba/F3-TEL-FGFR4V550L cells. Moreover, compound 19 exhibited potent antitumor potency in HUH7 xenograft mouse models with no obvious toxicity observed. Compound 19 was identified as a potential candidate for overcoming GK mutations for HCC treatment.

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling

“…The base-learners for FGFR1-V561M, FGFR2-N549H and FGFR3-V555M were expanded through fast adaption to recently reported compounds (Fig. 7b) 50,51,52,53,54,55,56 . Compared to the moderate performance of the original models of FGFR1-V561M and FGFR2-N549H, the performance of these finetuned models improved, while the performance of FGFR3-V555M remained consistently high (Fig.…”

Recent Advances in Synthetic Routes to Azacycles

“…Heterocyclic compounds are frequently identified and play an important role in human life due to their special structures. For example, heterocyclic structures are related to many biological processes and form the basic skeleton of many drug molecules and natural products [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. N -heterocycles, which contain nitrogen atoms, have attracted much attention from scientists because of their unique properties and diverse utilization.…”

Light-mediated sulfonyl-iodination of ynamides and internal alkynes

“…Sulfonyl moieties play an important role in pharmaceutics, medicinal chemistry, synthetic organic chemistry, drug discovery, and marketed drug production. 4 Moreover, the active C–I bond in the compounds offers great opportunities for alternative native chemical compounds. 5 Currently, there is no unique approach to access the selective four different natural sulfonyl-iodine-substituted olefins from ynamides or internal alkynes under sustainable conditions.…”