Deciphering the Potency and Pharmacokinetics of TG-1601: A Promising BET Inhibitor for Cancer Therapy

BET proteins are integral in gene transcription regulation, with their inhibition by small molecules able to selectively repress the transcription of certain oncogenes. TG-1601 is a newly developed, potent inhibitor of BET bromodomains, showing selectivity and high affinity for the first and second bromodomains of BET proteins, including BRD2, BRD3, BRD4, and BRDT, with dissociation constants (Kd) between 0.5 nM and 9.1 nM.

This compound has been shown to significantly reduce MYC protein expression in cancer cell lines, with a half-maximal inhibitory concentration (EC50) of 5 nM and a growth inhibitory concentration (GI50) ranging from 15 nM to 85 nM across various leukemia and myeloma cell lines. In vivo studies using MV4-11 xenograft-bearing mice revealed that a single oral dose of TG-1601 led to undetectable levels of MYC protein and a sustained effect even after the compound was cleared from the tumor, suggesting a long-lasting pharmacodynamic impact.

The long-lasting effect of TG-1601 was further supported by efficacy studies in mice, indicating that intermittent dosing schedules had minimal impact on therapeutic index (TGI). Additionally, TG-1601 demonstrated synergistic anti-tumor activity when combined with an anti-PD-1 antibody in a melanoma model, B16F10. The compound's inhibition of MYC, CCR-2, and IL1RN gene expression was validated as a means to monitor its activity clinically.

In summary, TG-1601 is characterized by its strong binding affinity, potent inhibition of MYC expression and cell growth, and favorable pharmacokinetics, which support its clinical development. The compound's in vivo profile offers a promising foundation for its development as an anti-cancer agent for use in monotherapy or combination with other therapeutics. IND-enabling studies were ongoing, with clinical trials anticipated to start in the first half of 2018.

The research was presented by Emmanuel Normant, Leonid Gorelik, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.