Insilico go in vivo with new promising and selective FGFR2/3 inhibitors
A new study in the Journal of Medicinal Chemistry reveals a promising drug candidate for the treatment of solid tumors.
Insilico Medicine (Boston; MA, USA) have published new research in the Journal of Medicinal Chemistry, detailing a series of novel fibroblast growth factor receptor (FGFR) inhibitors as potential therapeutics for the treatment of various solid tumors. FGFRs are a family of four tyrosine kinases, whose dysregulation is frequently associated with drug-resistant solid tumors, making them a popular target for medicinal chemists and drug designers.
Broad-spectrum FGFR inhibitors are already available on the market, however, their unselective targeting of FGFR1 and FGFR4 leads to unwanted side effects, such as diarrhea and elevated phosphate levels in the blood. Therefore, research has been focused on the development of an FGFR inhibitor selective for FGFR2 and FGFR3.
This is no easy feat, as the differences between the four kinases are minute, and they widely share a highly similar structure.
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Insilico medicine, as their name implies, are an organization focused on computational drug discovery, with an emphasis on generative artificial intelligence (AI)-led techniques. Their AI software, Chemistry42, played a pivotal role in generating the candidate molecules with suitable potency, selectivity and safety profiles for this investigation. The AI identified the heterocyclic pyrrolopyrazine carboxamide pharmacophore as best able to target the phosphate binding region of the proteins (the “P-loop”), that is highly similar in all four FGFR proteins. It also aided the development of a covalent electrophilic warhead to bind covalently to FGFR2/3.
Of 27 preliminary compounds synthesized for the fine-tuning of substituent chemical moieties branching from the scaffold, one molecule, compound 10, displayed by far the most promising initial results. Compound 10 was then taken forward for preclinical in vivo studies.
Animal model studies demonstrated that compound 10 possessed antitumor properties, high oral bioavailability and fewer side effects than existing, non-specific FGFR inhibitors. Moreover, it displayed a promising safety profile. Overall, the results were encouraging, revealing compound 10 as a strong candidate for further study.
If compound 10 makes the leap to clinical trials, it will join Insilico’s current portfolio of 10 molecules with FDA investigational new drug (IND) clearance, including their Traf2- and Nck- interacting kinase (TNIK) inhibitor, currently in a phase 2a trial as a therapeutic for pulmonary fibrosis.
