Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer.

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
Competing Interests: The updated Competing Interests are as follow:SF, CS, CM, DB and DZ are or have been employees and stakeholders of Cyclacel Ltd. PW, EM, BA, PS are or have been employees of The Institute of Cancer Research (ICR) which has a commercial interest in the discovery and development of CDK inhibitors and operates a rewards-to-inventors scheme. They have been involved in a commercial research collaboration with Cyclacel Limited and intellectual property arising from the program was licensed to Cyclacel. PW was a consultant/Scientific Advisory Board member to Cyclacel. PW was also involved in commercial research collaboration on CDK inhibitors with Merck KGaA and intellectual property was licensed to Merck KgA. PW was involved in commercial collaboration with Astex Pharmaceuticals and intellectual property was licensed to Astex. PW was a scientific founder, consultant, Scientific Advisory Board member and stock holder of Piramed Pharma (acquired by Roche) and intellectual property was licensed to Genentech. PW was a scientific founder, consultant, Scientific Advisory Board member, Board member and is a stockholder of Chroma Therapeutics and intellectual property was licensed to Chroma. PW is also a consultant/advisor to Astex Pharmaceuticals, CV6 Therapeutics and NextechInvest, and is a Non-Executive Director and stockholder of STORM Therapeutics. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.