Orally Effective CDK9 Inhibitor YX0798 for Treating Aggressive Lymphoma

Introduction

Non-genetic transcription evolution has been increasingly recognized as a contributor to tumor cell progression and therapeutic resistance. Transcriptomic reprogramming and tumor cell progression results from cyclin-dependent kinase 9 (CDK9) dysfunction, with CDK9 as the linchpin of transcription machinery through RNA polymerase II (Pol II) transcription. Our laboratory has recently shown that in mantle cell lymphoma (MCL), the HSP90-MYC-CDK9 network drives transcriptomic reprogramming, resulting in therapy resistance. We also showed AZD4573 and enitociclib are safe and effective treatments in preclinical MCL models, and the therapeutics target CDK9. However, current CDK9 therapeutic candidates could be improved by enhancing target selectivity and oral bioavailability.

Methods

In this study, we showcase a novel CDK9 inhibitor, YX0798, evaluating its potency and safety using preclinical MCL platforms and models. Molecular docking with Schrodinger was used to investigate the interaction of YX0798 with the CDK9 crystal structure. Binding assays with scanMAX were used to determine the selectivity of YX0798 across 468 kinases. Cell viability assays were conducted to assess in vitro efficacy. Apoptosis assays, western blots, and bulk RNA sequencing were used to determine the mechanism of action in MCL cells. Pharmacokinetic and pharmacodynamic profiling was conducted to determine the drug-like potential of YX0798. Patient-derived xenograft (PDX) models were used to determine the therapeutic potential of YX0798.

Results

The novel CDK9 inhibitor YX0798 have high target selectivity and good oral bioavailability. YX0798 demonstrated greater selectivity and greater affinity than commercial competitor in binding to CDK9. When administrated orally (5 mg/kg, daily), YX0798 led to even better anti-tumor activity in MCL resistance PDX models than the commercial competitor with intravenous injection at an equivalent dosing. Mechanistically, YX0798 or the commercial competitor led to CDK9 inhibition and primarily resulted in downregulation of short-lived oncoprotein c-MYC and pro-survival protein MCL-1. Ultimately, CDK9 inhibition disrupted the cell cycle and switched cellular metabolism towards oxidative phosphorylation, eventually leading to cell death.

Conclusions

Together, our study demonstrates that YX0798 is an orally bioavailable CDK9 inhibitor with exquisite selectivity and anti-tumor potency that drives transcription reprogramming towards tumor cell killing.

Wang:Scripps: Honoraria; Research to Practice: Honoraria; Physicians Education Resources: Honoraria; Juno Therapeutics: Research Funding; Pepromene Oncology: Consultancy; Praxel: Consultancy; Oncternal: Consultancy, Research Funding; Miltenyi Biomedicine: Consultancy; Lilly: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Studio ER Congressi: Honoraria; South African Clinical Hematology Society: Honoraria; WedMD: Honoraria; ADC Therapeutics: Consultancy; Amphista Therapeutics Limited: Consultancy; bE Biopharma: Consultancy; Deciphera: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Nurix: Honoraria; NIH: Honoraria; MSC National Research Institute of Oncology: Honoraria; Merck: Consultancy, Honoraria; MJH Life Sciences: Honoraria; Abbvie: Consultancy, Honoraria; BioInvent: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Genmab: Honoraria, Research Funding; Dava Oncology: Honoraria; Catamount Medical Education: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding.