1. Academic Validation
  2. Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

  • J Med Chem. 2024 Jan 11;67(1):420-432. doi: 10.1021/acs.jmedchem.3c01476.
Yazhou Wang 1 Chao Wang 1 Tingting Liu 1 Hongyun Qi 1 Shan Chen 1 Xin Cai 1 Man Zhang 1 Alex Aliper 2 Feng Ren 1 Xiao Ding 1 Alex Zhavoronkov 1 2
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2 Insilico Medicine AI Limited, Masdar City 145748, Abu Dhabi, United Arab Emirates.
Abstract

Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating the urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target for breast and gynecological Cancer using PandaOmics, an AI-driven target discovery platform. The synthetic lethal relationship of MYT1 in tumor cell lines with CCNE1 amplification enhanced this rationale. Through structure-based drug design, we developed a series of novel, potent, and highly selective inhibitors specifically targeting MYT1. Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over Wee1, a related kinase associated with bone marrow suppression upon inhibition. Optimization of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic properties and promising in vivo antitumor efficacy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157443
    Myt1 Inhibitor