PK/PD and preclinical ADME characterization of TB-008, a first-in-class CDK9 degrader in xenograft models

Targeted protein degradation (TPD) offers a promising therapeutic strategy by removing, rather than inhibiting, disease-driving proteins. Cyclin-dependent kinase 9 (CDK9) is a key oncogenic regulator implicated in multiple hematologic and solid tumors. TB008 is a rationally designed CDK9-targeting PROTAC developed using an AI-driven degrader platform to achieve high affinity, selectivity, and favorable pharmacologic properties. Preclinical studies have demonstrated potent, selective CDK9 degradation with downstream suppression of oncogenic targets such as c-MYC and MCL-1. TB008 has shown robust antiproliferative and pro-apoptotic activity across cancer cell lines and strong tumor growth inhibition >95% in triple negative breast cancer xenograft model which support further development of TB008 as a CDK9-directed therapeutic candidate. Pharmacokinetics in Balb/c-nude mice (efficacy study species) has shown that TB-008 is rapidly absorbed following an intraperitoneal dose with ~90% bioavailability and a half-life of 1 hr. Interestingly, in-silico PK and bioavailability analysis does predict that there is a 90% decrease in drug concentration in mouse plasma within the first hour after administration. Furthermore, also based on in-silico evaluation, it is also predicted that higher drug concentration will be in the GI tract, lungs, plasma, spleen and portal vein. Even with the relatively short half-life, the high tumor growth inhibition observed in xenograft studies confirms the potency and fast kinetics of TB-008 in effecting the degradation of the tumor CDK9. We have initiated studies in mouse xenograft models to better understand the PK/PD and design optimal dosing regimens. Also, we will report the efficacy of TB-008 in additional xenograft models. Additional preclinical ADME data and PK in higher nonclinical species will be reported.