Exploring the Therapeutic Potential of TQB3728: A Novel IAP Antagonist in Preclinical Cancer Models

The inhibitor of apoptosis (IAP) proteins are crucial in cancer's ability to evade apoptosis and avoid immune surveillance, making them significant targets for cancer therapy. Smac mimetic compounds (SMCs), antagonists of IAPs, are advancing rapidly in clinical development. A new SMC, TQB3728, has been introduced and evaluated for its potential in tumor therapy.

TQB3728's biochemical activity was assessed through specific assays for cIAP1 BIR3, cIAP2 BIR3, and XIAP BIR3, showing potent results with low IC50 values. The compound also exhibited anti-proliferative effects on MDA-MB-231 and EMT6 cancer cell lines, with notable IC50 values in the presence of TNFα.

In vivo testing of TQB3728's antitumor activity was conducted using xenograft models of triple-negative breast cancer (TNBC) and lymphoma, as well as a syngeneic model of TNBC. The compound demonstrated significant tumor growth inhibition (TGI) in the MDA-MB-231 model, outperforming the SMC LCL-161. Additionally, TQB3728 showed robust antitumor effects in the Karpas 422 lymphoma model and, in combination with an anti-PD1 antibody, significantly regressed tumor growth in EMT6 tumor-bearing mice.

Pharmacokinetic and pharmacodynamic (PK/PD) assessments through western blot analysis indicated that TQB3728 promotes caspase 3 cleavage, suggesting that its antitumor effects may be mediated through the induction of cell apoptosis.

In conclusion, TQB3728 has been identified as a potent oral IAP antagonist with significant in vitro and in vivo antitumor activity. The compound's ability to inhibit cIAP1 and its strong antitumor effects in preclinical models are highly encouraging and support the progression of TQB3728 to clinical investigation.