Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma

  • Blood Neoplasia. 2024 Oct 24;2(1):100050. doi: 10.1016/j.bneo.2024.100050.
Son Tran  1 ,  Patrick Sipila  1 ,  Melanie M Frigault  2 ,  Beatrix Stelte-Ludwig  3 ,  Amy J Johnson  2 ,  Joseph Birkett  3 ,  Raquel Izumi  2 ,  Ahmed Hamdy  2 ,  Ranjan Maity  4 ,  Nizar J Bahlis  4 ,  Paola Neri  4 ,  Aru Narendran  1
Affiliations
  • 1. Department of Oncology, University of Calgary, Calgary, AB, Canada.
  • 2. Vincerx Pharma, Inc, Palo Alto, CA.
  • 3. Vincerx Pharma GmbH, Monheim, Germany.
  • 4. Departments of Hematology and Oncology, University of Calgary, Calgary, AB, Canada.
PMID: 40546728 DOI: 10.1016/j.bneo.2024.100050
Abstract

Multiple myeloma (MM) is a Cancer of plasma cells that remains incurable despite advances in treatment options. In this study, a library of 216 clinically feasible small-molecule inhibitors was screened to identify agents that selectively inhibit MM cell proliferation. Enitociclib, a cyclin-dependent kinase 9-specific small-molecule inhibitor, was found to be highly effective in decreasing cell viability and inducing Apoptosis in 4 MM cell lines. Enitociclib inhibited the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II at Ser2/Ser5 and repressed the protein expression of oncogenes c-Myc, myeloid cell leukemia-1 (Mcl-1), and proliferating cell nuclear antigen (PCNA) in MM cells. Additionally, enitociclib demonstrated synergistic effects with several anti-MM agents, including bortezomib, lenalidomide, pomalidomide, and venetoclax. These results suggest that enitociclib may represent a promising therapeutic option for the treatment of MM, either as a single agent or in combination with Other anti-MM agents.

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