A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies

Abstract

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.

Emerging agents and regimens for AML

“…Given the proven synergies of BCL-2 inhibition, multiple combinations with targeted agents, and venetoclax are under investigation. There are many ongoing combinations of therapies targeting BCL-2 and other pathways, including FLT3 inhibitors (gilteritinib) and IDH1 and 2 inhibitors (Ivosidenib and enasidenib) (will be discussed in the later sections), MCL-1 inhibitors (VU661013, A-1210477); MEK1/2 inhibitor (cobimetinib), and MDM2 inhibitor (idasanutlin) (reviewed in [ 20 ]), combination with TKI in Ph + acute leukemia [ 21 ] and other emerging pre-clinical combinations including small-molecule inhibitors of CDK9 (the orally active A-1592668 and the related analog A-1467729) leading to down-expression of MCL-1 [ 22 ]; the Exportin inhibitor, Selinexor, [ 23 ]; BET inhibitors, ABBV-075, [ 24 ]; SRC family kinases (SFK) and Bruton's tyrosine kinase (BTK) inhibitor, ArQule 531 (ARQ 531), [ 25 ]; and it is expecting much more novel combinations to come.…”

Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

“…In primary AML cells, combining the MCL-1 inhibitor S63845 with VEN results in greater efficacy than either inhibitor alone, with a more potent activity against leukemic rather than normal hematopoietic progenitors 68 . In an AML patient-derived xenograft mouse model bearing FLT3 -ITD, the CDK9 inhibitor A-1592668 combined with VEN provided a significant survival advantage over single treatments 69 . In a lymph node mimicking microenvironment, fadraciclib in combination with VEN for 24 h efficiently induced apoptosis of primary CLL cells 70 , a disease where MCL-1 plays a role in disease progression and fludarabine resistance 71 .…”

The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action

“…1B ). It was reported that compounds that reduced Mcl-1 levels caused synergistic cell death when combined with the Bcl-2 antagonist venetoclax 17 , 19 , 34 , 45 . However, we did not see a synergistic combination effect when TG02 and venetoclax were used together (Supplementary Fig.…”

“…Direct inhibition of Mcl-1 9 or specific knocking down Mcl-1 by siRNA 10 induced apoptosis in CLL cells. We and others showed that the CDK9 inhibitors roscovitine 11 , flavopiridol 12,13 , SNS-032 14,15 , dinaciclib 16 as well as the new agents such as voruciclib 17,18 , A-1592668 19 and AZD4573 20 , blocked the phosphorylation of RNA pol II which inhibited transcription 21,22 . This action reduced Mcl-1 and induced apoptosis in CLL cells.…”