Delving into the Latest Updates on YJZ-5118 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CDK12 x CDK13

Action

inhibitors

Mechanism

CDK12 inhibitors(cyclin dependent kinase 12 inhibitors), CDK13 inhibitors(cyclin dependent kinase 13 inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Prostatic Cancer

Inactive Indication-

Originator Organization

Jinan University

Active Organization

Jinan University

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC36H44N8O2

InChIKeyDPTMMKXNCQVAJW-UNWRIRMBSA-N

CAS Registry3031861-18-1

Author: Ren, Xiaomei ; Ervine, Grafton ; Zhou, Yang ; Ding, Ke ; Chang, Yu ; Zhou, Licheng ; Huang, Weixue ; Mannan, Rahul ; Yang, Jianzhang ; Zhou, Kaijie ; Zhang, Pujuan ; Wang, Zhen ; Hamadeh, Rudana ; Tien, Jean Ching-Yi ; Zhang, Yuping ; Wang, George Xiaoju ; Chinnaiyan, Arul M. ; Mahapatra, Somnath ; Liu, Wenyan

Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of YJZ5118, a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. YJZ5118 effectively inhibited CDK12 and CDK13 with IC₅₀ values of 39.5 and 26.4 nM, respectively, while demonstrating high selectivity over other CDKs. Mass spectrometry analysis, cocrystal structure determination, and pulldown-proteomic experiments confirmed the compound's covalent binding mode with CDK12/13. Functionally, YJZ5118 efficiently suppressed the transcription of DNA damage response genes, induced DNA damage, and triggered apoptosis. Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate cancer cells. Notably, YJZ5118 exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.

100 Deals associated with YJZ-5118

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