Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor

by Selleckchem | Dec 02 2023

Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.

Comments:

It sounds like you are describing the successful development of a novel compound (Compound 40 or JSH-150) through a structure-guided rational drug design approach. Here's a summary of the key findings and implications of your discovery:

1. **Target Specificity:** Compound 40 (JSH-150) has been found to be highly selective, inhibiting CDK9 kinase with an IC50 of 1 nM. It exhibited significant selectivity (around 300-10000-fold) over other members of the CDK kinase family, as well as over a wide range of other kinases/mutants (KINOMEscan S score(1) = 0.01).

2. **Antiproliferative Effects:** The compound demonstrated potent antiproliferative effects across various cancer cell lines, including melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer, and leukemia. It achieved this by inhibiting the phosphorylation of RNA Pol II, suppressing the expression of MCL-1 and c-Myc, arresting the cell cycle, and inducing apoptosis in leukemia cells.

3. **In Vivo Efficacy:** In a mouse model (MV4-11 cell-inoculated xenograft), a dosage of 10 mg/kg of Compound 40 almost completely suppressed tumor progression, indicating strong in vivo efficacy.

4. **Pharmacological Tool and Drug Candidate:** Due to its high selectivity and good in vivo pharmacokinetic/pharmacodynamic (PK/PD) profile, Compound 40 is considered a valuable pharmacological tool for studying CDK9-mediated physiology and pathology. Moreover, it holds promise as a potential drug candidate for leukemia and other cancers.

In summary, Compound 40 (JSH-150) represents a significant advancement in the field of cancer research. Its high selectivity, potent antiproliferative effects, and in vivo efficacy make it a promising candidate for further studies and potential clinical applications in the treatment of leukemia and other cancer types.