YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma

ABSTRACT Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activity in vivo and showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing. KEY POINTS YX0798 showed high selectivity, target binding affinity, and anti-tumor efficacy in overcoming resistance to various therapies. YX0798 had good oral pharmacokinetics and anti-tumor effects that resulted from transcription reprogramming towards tumor cell killing.