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Updated: Oct 10, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.2K

Discovery of spiro amide SHR902275: A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers

Peng Zhao1, Linghang Zhuang1, Xiangzhu Wang1

  • 1Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, NJ, 08512, USA.

European Journal of Medicinal Chemistry
|December 15, 2021
PubMed

Insights

Researchers developed a new RAF inhibitor, molecule 33, to combat cancer drug resistance by targeting the RAS-RAF-MEK-ERK pathway. This novel compound shows promising efficacy in preclinical models and improved drug properties.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • The RAS-RAF-MEK-ERK pathway regulates cellular functions, and resistance to RAF inhibitors is a significant challenge in cancer therapy.
  • First-generation RAF inhibitors targeting bRAF V600E mutations are limited, necessitating new strategies for cancers with mutant RAS and wild-type RAF.
  • Inhibition of paradoxical activation is a key strategy for next-generation RAF inhibitors.

Purpose of the Study:

  • To discover and optimize novel RAF inhibitors effective against cancers with mutant RAS.
  • To develop a compound with improved potency, solubility, and pharmacokinetic properties compared to existing inhibitors.
  • To evaluate the in vivo efficacy and drug-like properties of the newly discovered molecule.

Main Methods:

  • Structure-based drug design and medicinal chemistry optimization of a previously reported RAF inhibitor.
  • In vitro assays to assess potency, solubility, and drug metabolism and pharmacokinetics (DMPK).
  • In vivo studies using a RAS mutant Calu6 xenograft mouse model to evaluate anti-tumor efficacy.
  • Exploration of a pro-drug strategy to achieve higher exposure in toxicity studies.

Main Results:

  • Discovery of molecule 33 (SHR902275) with significantly enhanced in vitro potency and solubility.
  • Molecule 33 demonstrated favorable DMPK properties, excellent permeability, and outstanding oral pharmacokinetics in rodents.
  • Dose-dependent anti-tumor efficacy was observed in a RAS mutant Calu6 xenograft mouse model.
  • A pro-drug (molecule 48) was synthesized to improve exposure for toxicity assessments.

Conclusions:

  • Molecule 33 represents a promising next-generation RAF inhibitor candidate for treating cancers with RAS mutations.
  • The optimized compound exhibits a strong preclinical profile, including efficacy and favorable pharmacokinetic properties.
  • Further development, including pro-drug strategies, is warranted to advance this molecule towards clinical application.
Keywords:
Kinase inhibitorMutationParadoxical activationRAFRASSpiro compound

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