2. Academic Validation
  3. Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy

Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy

  • J Med Chem. 2024 Nov 28;67(22):20580-20594. doi: 10.1021/acs.jmedchem.4c02098.
Hongfu Lu 1,  Yihong Zhang 1,  Jinxin Liu 1,  Tao Jiang 2,  Xiang Yu 3,  Haoyu Zhang 1,  Tao Liang 3,  Jingjing Peng 1,  Xin Cai 1,  Xiaoling Lan 3,  Jinmin Ren 3,  Mei Ge 3,  Jingyang Zhang 3,  Jingjin Shang 3,  Jiaojiao Yu 1,  Hongcan Ren 3,  Qiang Liu 3,  Jinting Gao 3,  Lili Tang 3,  Xiao Ding 1,  Man Zhang 1,  Alex Aliper 4,  Qiang Lu 3,  Fusheng Zhou 3,  Jiong Lan 3,  Feng Ren 1,  Alex Zhavoronkov 1 4
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2 GenFleet Therapeutics (Zhejiang) Co Ltd., Shaoxing, 312000, P.R. China.
  • 3 GenFleet Therapeutics (Shanghai) Inc., Shanghai 201203, P.R. China.
  • 4 Insilico Medicine AI Limited, Masdar City, Abu Dhabi 145748, UAE.
PMID: 39520367 DOI: 10.1021/acs.jmedchem.4c02098
Abstract

Cyclin-dependent kinase 7 (CDK7) is a key regulator of the cell cycle and transcription, making it a promising target for Cancer therapy. Although current CDK7 inhibitors have improved in their selectivity and druglike properties, CDK7 inhibitors have failed to progress through clinical development due to severe gastrointestinal and hematotoxic side effects. To mitigate these limitations, we have developed novel, macrocyclic, noncovalent CDK7 hit compounds 2 and 3 using a macrocyclization platform that has optimized these compounds from SY-5609, a leading clinical asset. We conducted extensive structure-activity relationship (SAR) studies to improve their potency, enhance oral bioavailability, and reduce intestinal distribution, which resulted in compound 13. Compound 13 exhibits potent in vitro activity, good ADME properties, and robust in vivo antitumor activity in xenograft models as a monotherapy. Notably, compound 13 with lower basicity demonstrated improved Caco-2 permeability, reduced blood/plasma ratio, and reduced intestinal distribution in rats, thus mitigating gastrointestinal and hematotoxic side effects.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169344
    CDK7 抑制剂
    CDK
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