BioTheryx’s small-molecule kinase inhibitor, BTX-A51 (the ditosylated salt of A51), has recently received FDA approval of its IND application to initiate a Phase I clinical trial in relapsed or refractory acute myeloid leukemia (AML). A51 (API of BTX-A51) is a multi-kinase inhibitor that blocks the leukemic stem cell target, Casein Kinase 1α (CK1α), as well as the super-enhancer regulator, Cyclin-Dependent Kinase 9 (CDK9), thus preventing the transcription of key oncogenic genes. This molecule has demonstrated remarkable preclinical animal efficacy inferring the eradication of AML stem cells and its potential for use in treating multiple malignancies. To exploit the unique properties of this multi-kinase inhibitor in the context of kinase protein degradation, Proteolysis-Targeting Chimeras (PROTACs) of A51 were investigated. As a reversible kinase inhibitor, A51 binds stoichiometrically to CK1α and CDK9 and requires continuous occupancy of these proteins to sustain its unique inhibitory activity. A PROTAC of A51, however, would act catalytically and ablate the target proteins. In this study, PROTACs were assembled through chemically linking A51 to BioTheryx’s proprietary Protein Homeostatic Modulators (PHMsTM). PHMsTM are a new class of small molecules which bind to the E3 ubiquitin ligase, Cereblon (CRBN), and promote proteasomal degradation of known as well as unreported clinically-relevant CRBN neo-substrates. For the discovery of PHM®-A51 PROTACs, CDK9 crystal structure (6GZD.pdb) and CRBN crystal structure (5FQD.pdb) were used independently for computational drug design. Upon testing in AML and lymphoma cell lines, the PHM®-A51 PROTACs rapidly induced the degradation of both CK1α and CDK9. The PHM®-A51 PROTACs have demonstrated low-nanomolar inhibition of cell proliferation in both AML and lymphoma cell lines yet have significantly less toxicity in fibroblast cells and PBMCs. In addition, this class of PROTACs has good pharmaceutical properties, as demonstrated by pharmacokinetic studies in mice, and will advance into AML and lymphoma in vivo studies. The targeted degradation of CK1α and CDK9 using safe, bioavailable drugs designed using strategically-selected PHMsTM with unique biological properties of their own is a very promising approach to treating hematological malignancies and other devasting cancers.

Bioavailable dual-protein degraders of CK1α and transcriptional kinase CDK9 as potential therapeutics for hematological malignancies

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.