Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin- dependent kinases (CDKs)

Abstract

Abstract A fundamental aspect of cancer is the dysregulation of cell cycle control, which is associated with selective, aberrant activation of cyclin-dependent kinases (CDK). Consequently, targeting CDKs represents an attractive therapeutical approach for cancer therapy. Pan-CDK inhibitors block the cell cycle and inhibit proliferation, but their major drawback is the lack of selectivity and high toxicity in healthy tissues. Therefore, there is a demand for the development of new bioactive molecules with anticancer properties, such as the compound class of Meriolins. Meriolins are a semisynthetic compound class derived from Meridianins and Variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives Meriolin 16 and Meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we identified that Meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of Meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for Meriolin 36. We could show that cell cycle progression and proliferation were blocked due to the abolished phosphorylation of the main CDK2 target Retinoblastoma protein at Ser612 and Thr821. Moreover, Meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (i) inhibition of cell cycle progression and proliferation, (ii) prevention of transcription, and (iii) induction of cell death.