Related Experiment Video

Updated: Jun 13, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.3K

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in

Jianzhang Yang1,2, Yu Chang3, Kaijie Zhou1

  • 1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.

Journal of Medicinal Chemistry
|March 13, 2025
PubMed

Insights

A new drug, YJZ5118, potently and selectively inhibits cyclin-dependent kinases 12 and 13 (CDK12/13), offering a promising therapeutic strategy for cancers like castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinases 12 and 13 (CDK12/13) are key targets in oncology.
  • Existing CDK12/13 inhibitors face challenges in balancing potency, selectivity, and pharmacokinetics.

Purpose of the Study:

  • To discover and characterize YJZ5118, a novel, potent, and selective covalent inhibitor of CDK12/13.
  • To evaluate the therapeutic potential of YJZ5118 in preclinical cancer models.

Main Methods:

  • In vitro kinase inhibition assays to determine IC50 values.
  • Mass spectrometry, cocrystal structure determination, and pulldown-proteomic experiments for binding mode analysis.
  • Cell-based assays to assess gene transcription, DNA damage, apoptosis, and proliferation inhibition.

Main Results:

  • YJZ5118 demonstrated potent inhibition of CDK12 (IC50=39.5 nM) and CDK13 (IC50=26.4 nM) with high selectivity.
  • Confirmed covalent binding mode of YJZ5118 to CDK12/13.
  • YJZ5118 suppressed DNA damage response genes, induced DNA damage, triggered apoptosis, and inhibited tumor cell proliferation, particularly in prostate cancer.
  • Synergistic effects observed with Akt inhibitors in vitro and in vivo.

Conclusions:

  • YJZ5118 is a novel covalent CDK12/13 inhibitor with favorable properties for cancer therapy.
  • YJZ5118 effectively targets key cancer pathways and shows promise in combination therapies.

More Related Videos

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.1K
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach11:11

Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach

Published on: February 21, 2019

7.4K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.5K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.1K