VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia

Author:

Sher StevenORCID,Whipp EthanORCID,Walker Janek,Zhang Pu,Beaver Larry,Williams Katie,Orwick ShelleyORCID,Ravikrishnan Janani,Walker Brandi,Perry Elizabeth,Gregory CharlesORCID,Purcell Matthew,Pan Alexander,Yan PearllyORCID,Alinari Lapo,Johnson Amy J.,Frigault Melanie M.,Greer Joy M.,Hamdy Ahmed,Izumi Raquel,Mo XiaokuiORCID,Sampath DeepaORCID,Woyach JenniferORCID,Blachly JamesORCID,Byrd John C.,Lapalombella RosaORCID

Abstract

AbstractChronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Publisher

Springer Science and Business Media LLC

Subject

Oncology,Cancer Research,Hematology

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