Efficacy of the novel CDK7 inhibitor QS1189 in mantle cell lymphoma.

Abstract

Mantle cell lymphoma (MCL) is typically an aggressive and rare form of non-Hodgkin lymphoma (NHL) with a poor prognosis despite recent advances in immunochemotherapy and targeted therapeutics against NHL. New therapeutic agents are needed for MCL. In this study, we generated a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated QS1189, and confirmed its anti-cancer effects towards MCL and other lymphomas. QS1189 was highly selective for CDK7 and showed potent anticancer effects in MCL compared to other targeted therapeutic agents, such as ibrutinib and venetoclax. Consistent with a conventional CDK7 inhibitor, QS1189 treatment significantly decreased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and transcription-associated genes. QS1189 induced cell cycle arrest at the G2/M phase and apoptosis. Interestingly, QS1189 overcame the acquired resistance to venetoclax, which is mediated by Bcl-xL. Similarly, QS1189 showed potent tumour cell growth inhibition of various lymphomas. Thus, CDK7 might be a suitable therapeutic target for inhibiting lymphoma, and QS1189 is a promising therapeutic option for various lymphomas and cells with acquired resistance to targeted therapy.

• Authors: Yun Jung Choi, Dong Ha Kim, Dok Hyun Yoon, Cheolwon Suh, Chang-Min Choi, Jae Cheol Lee, Jung Yong Hong, Jin Kyung Rho
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 7193 (05 10 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31076643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Piperidines
• Pyrazoles
• Pyrimidines
• Sulfonamides
• Triazoles
• ibrutinib
• Cyclin-Dependent Kinases
• RNA Polymerase II
• Adenine
• venetoclax
• Cyclin-Dependent Kinase-Activating Kinase
• CDK7 protein, human

Topics

• Adenine (analogs & derivatives)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Humans
• Lymphoma, Mantle-Cell (drug therapy, metabolism)
• Phosphorylation (drug effects)
• Piperidines
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA Polymerase II (chemistry, metabolism)
• Sulfonamides (pharmacology)
• Triazoles (chemical synthesis, chemistry, pharmacology)
• Cyclin-Dependent Kinase-Activating Kinase