Abstract 3811: Drug discovery of potent and specific CDK9 protein degraders for the treatment of refractory lymphomas

Abstract Introduction: CDK9, a core component of positive transcription elongation factor b (p-TEFb) playing a crucial role in RNA polymerase II transcription (RNAP II) initiation to elongation, is a promising target for treating refractory lymphomas. MYC and CDK9 are overexpressed in BTK inhibitor (BTKi) and CAR-T dual-resistance mantle cell lymphoma (MCL) patient samples, which is associated with the progression of this disease. Targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Proteolysis Targeting Chimera (PROTAC) represents an emerging pharmacological modality with significant advantages over traditional inhibitors. Developing potent and specific CDK9 degraders may offer a unique therapeutic approach for the treatment of refractory lymphomas including incurable MCL. Methods: To discover potent and specific CDK9 binders, we performed a rational design and structure-based optimization of available clinical scaffolds. To construct CDK9 PROTACs, we adopted our identified CDK9is, clinical candidates AZD4573 and VIP152, conjugating with E3 ligands via diverse linkers for comparison studies. Extensive in vitro pharmacological evaluations using cellular and biochemical assays were performed. The in vivo efficacy of the promising candidates was determined using patient-derived xenograft (PDX) models. Results: YX0798 was discovered as one of the most potent and selective CDK9is and binders, with a high binding affinity (Kd = 0.28 nM) and high specificity (Kinome panel assay), superior to AZD4573. YX0798 is highly effective against various MCL cell lines (IC50s = 26 to 110 nM), with low toxicity toward PBMCs. YX0798 significantly inhibits cellular CDK9 phosphorylation, induces PARP and caspase 3 cleavage, and reduces anti-apoptotic Mcl-1 in Z138 cell. YX0798 is also orally bioavailable. Several candidates such as YX0597 were identified as potent and specific protein degraders, effective against BTKi-resistant MCL cells and inducing cell apoptosis. YX0597 significantly suppresses the tumor growth in a PDX mouse model with dual resistance to BTKi and CAR-T without causing mouse body weight loss. The effective dosage of YX0597 is as low as 1 mg/kg (IP, QD, 5 days only), and much lower than AZD4573 (15+15 mg/kg, 2h apart, IP, QW, 6 weeks). Conclusion: Through rational drug design and structure-based chemical optimization, YX0798 was discovered as a novel CDK9i with high binding affinity, cellular potency, target specificity, and favorable PK properties. Several promising potent and specific CDK9 degraders such as YX0597 have been identified. YX0597 is a bona fide CDK9 degrader highly effective against various resistant MCL cells, induces cell apoptosis and suppresses the tumor growth in vivo at a very low dosage in a PDX mouse model with dual resistance to BTKi and CAR-T, indicating its potential for the treatment of refractory lymphomas including resistant MCL. Citation Format: Yu Xue, Vivian Jiang, Haiying Chen, Hong Kim, Tianci Zhang, Qingsong Cai, Lei Nie, Joseph McIntosh, Yang Liu, Michael Wang, Jia Zhou. Drug discovery of potent and specific CDK9 protein degraders for the treatment of refractory lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3811.