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-1-dependent 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.
Highlights
Cyclin-dependent kinases (CDKs) are serine–threonine kinases that function to coordinate multiple cellular
A-1592668 demonstrated robust pharmacodynamic marker movement and cell killing in MCL-1 dependent cell lines (Table 1), yet spared non-MCL-1 dependent cell lines (Supplementary Table 1; [34]), phenocopying the in vitro effects of A-1467729 and indicating that cell killing in H929 and MV4-11 cells was driven via inhibition of CDK9
Previously published preclinical data highlight the contributions of BCL-2 and BCL-XL in maintaining the survival of these malignancies [34, 17, 19, 36], which may limit the breadth of single agent CDK9 inhibitor activity
Summary
Cyclin-dependent kinases (CDKs) are serine–threonine kinases that function to coordinate multiple cellular. Among CDK9 inhibitors, flavopiridol has been studied most extensively in the clinic; while trials with this agent have shown encouraging clinical efficacy, a complex toxicity profile associated with activity beyond CDK9 has hampered development [3]. The consequence of this promiscuity has been elegantly demonstrated in T98G glioblastoma cells, where introduction of a kinase-dead, dominant-negative mutant CDK9 results in a gene expression profile that is distinct from that induced by flavopiridol [26]. An additional goal of this program was to generate compounds with oral activity to enable the option of an all oral regimen for treating BCL-2, MCL-1 co-dependent tumors
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