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

Area of Science:

• Oncology
• Pharmacology

Background:

• Multiple myeloma (MM) is an incurable plasma cell cancer.
• Current treatments face limitations, necessitating novel therapeutic strategies.

Purpose of the Study:

• To screen small-molecule inhibitors for selective MM cell proliferation inhibition.
• To evaluate enitociclib, a CDK9 inhibitor, as a potential MM treatment.

Main Methods:

• Screened 216 clinically feasible small-molecule inhibitors.
• Assessed enitociclib's effects on MM cell viability and apoptosis.
• Investigated enitociclib's molecular mechanisms, including RNA polymerase II CTD phosphorylation and oncogene expression.
• Evaluated synergistic effects with standard MM agents.

Main Results:

• Enitociclib significantly decreased MM cell viability and induced apoptosis in four MM cell lines.
• Enitociclib inhibited RNA polymerase II CTD phosphorylation at Ser2/Ser5.
• Enitociclib repressed c-Myc, Mcl-1, and PCNA protein expression in MM cells.
• Enitociclib demonstrated synergistic effects with bortezomib, lenalidomide, pomalidomide, and venetoclax.

Conclusions:

• Enitociclib is a potent CDK9 inhibitor with selective activity against MM cells.
• Enitociclib targets key pathways involved in MM cell proliferation and survival.
• Enitociclib warrants further investigation as a single agent or in combination therapy for MM.