TY - JOUR
T1 - VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia
AU - Sher, Steven
AU - Whipp, Ethan
AU - Walker, Janek
AU - Zhang, Pu
AU - Beaver, Larry
AU - Williams, Katie
AU - Orwick, Shelley
AU - Ravikrishnan, Janani
AU - Walker, Brandi
AU - Perry, Elizabeth
AU - Gregory, Charles
AU - Purcell, Matthew
AU - Pan, Alexander
AU - Yan, Pearlly
AU - Alinari, Lapo
AU - Johnson, Amy J.
AU - Frigault, Melanie M.
AU - Greer, Joy M.
AU - Hamdy, Ahmed
AU - Izumi, Raquel
AU - Mo, Xiaokui
AU - Sampath, Deepa
AU - Woyach, Jennifer
AU - Blachly, James
AU - Byrd, John C.
AU - Lapalombella, Rosa
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - Chronic 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.
AB - Chronic 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.
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U2 - 10.1038/s41375-022-01758-z
DO - 10.1038/s41375-022-01758-z
M3 - Article
C2 - 36376377
AN - SCOPUS:85141835814
SN - 0887-6924
VL - 37
SP - 326
EP - 338
JO - Leukemia
JF - Leukemia
IS - 2
ER -