Efficacy of the novel CDK7 inhibitor QS1189 in mantle cell lymphoma

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.