Abstract B125: Discovery of a first-in-class CDK9 degrader targeting oncogenic transcription networks in hematologic and solid tumors

Abstract Targeted protein degradation (TPD) is potentially a highly promising approach to drug discovery, offering advantages over conventional inhibition by eliminating disease-driving proteins. The lead Proteolysis Targeting Chimera (PROTAC) candidate, TB008, is a rationally designed degrader that targets cyclin dependent kinase 9 (CDK9), an oncogenic transcription factor implicated in both hematologic malignancies and solid tumors. TB008 has been developed using Therabene’s AI-driven proprietary degrader platform, optimized for high-affinity binding, selective degradation, and favorable pharmacologic properties. TB008 has been evaluated in a panel of human cancer cell lines representative of hematologic and solid tumors, measuring cell viability and apoptosis. Degrader activity was confirmed via western blot. In-vivo efficacy was assessed using xenograft mouse models, with tumor growth inhibition (TGI) as endpoint. TB008 was potent and selectively caused time-dependent, rapid and direct degradation of CDK9 in the nanomolar range and caused no degradation in CDK1, CDK2, CDK4, CDK6 and CDK7. It also led to indirect degradation of downstream targets such as c-MYC and MCL-1 proteins in a time-dependent manner. Treatment with TB008 led to significant reduction in cell proliferation, and induced apoptosis in several human cancer cell lines, including HCC1187 [triple negative breast cancer (TNBC)], NCI-H358 (lung cancer), and MIA-PaCa-2 (pancreatic cancer). In-vivo, TB008 was administered intraperitoneally (IP) at 20mg/Kg daily for the first week and then every other day for weeks 2 and 3, in mice bearing HCC1187 tumors (N=7 per group). This led to >95% TGI by the end of dosing at day 24 and continued to display tumor suppression till end of study at day 48. Furthermore, 2/7 (∼30%) mice showed tumor regression. Treatment was well-tolerated with no evidence of body weight loss. The backup candidate, TB003B also showed similar in-vivo efficacy. TB008 is a promising first-in-class PROTAC with robust anti-tumor activity in vitro and in vivo. These preclinical results support its advancement toward IND-enabling studies. Citation Format: Isabelle Dussault, Narayana Narasimhan, Mahesh Koirala, Trisha Lahiry, Lindy Yan, Zoser Mohamed, Mario DiPaola. Discovery of a first-in-class CDK9 degrader targeting oncogenic transcription networks in hematologic and solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B125.