Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3

Shvartsbart, Artem; Roach, Jeremy J.; Witten, Michael R.; Koblish, Holly K.; Harris, Jennifer J.; Covington, Maryanne; Hess, Rodrigo; Frascella, Michelle; Truong, Lisa; Leffet, Lynn; Conlen, Patricia; Beshad, Elham; Klabe, Ron; Katiyar, Kamna; Kaldon, Laura; Young-Sciame, Ruth; He, Xin; Petusky, Susan; Chen, Kwang-Jong; Horsey, April; Lei, Hanlun; Epling, L.B.; Deller, Marc C.; Vechorkin, Oleg; Yao, Wenqing

doi:10.1021/acs.jmedchem.2c01366

Cited by 9 publications

(5 citation statements)

References 20 publications

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“…Recently, only a few examples of FGFR2 selective inhibitors in the early stages have been reported. 27,28 PROTAC technology has displayed incredible potential as a protein degradation strategy, with striking advantages compared to traditional inhibitors. 20 PROTAC-induced degradation requires the formation of ternary complexes, targeted ubiquitination, and degradation via the proteasome.…”

Section: Discussionmentioning

confidence: 99%

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Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Luo

et al. 2023

J. Med. Chem.

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Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.

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Section: Discussionmentioning

confidence: 99%

“…Currently, it is still challenging to identify specific isoform-selective inhibitors owing to their highly conserved kinase domains. Recently, only a few examples of FGFR2 selective inhibitors in the early stages have been reported. , …”

Section: Discussionmentioning

confidence: 99%

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Luo

et al. 2023

J. Med. Chem.

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“…Other benefits of deuteration that are emerging — but are still not completely understood — include a potential effect of D on both drug–target interactions (as discussed above) and time-dependent inhibition of CYP enzymes 140 – 143 . Inhibition of cytochromes is undesirable in drug R&D as it might lead to drug–drug interactions in patients undergoing multiple therapies.…”

Section: Opportunities and Challenges For Deuterationmentioning

confidence: 99%

Deuterium in drug discovery: progress, opportunities and challenges

Martino

Maxwell

Pirali

2023

Nat Rev Drug Discov

184

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Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.

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“…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.…”

Section: Retrospective Analysis Of the Inhibitors Targeting Understud...mentioning

confidence: 99%

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling

Ren

Sun

et al. 2023

Preprint

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Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for PKMYT1 and selective inhibitors for drug-resistant mutants of FGFRs demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.

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Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3

Cited by 9 publications

References 20 publications

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Deuterium in drug discovery: progress, opportunities and challenges

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling

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