Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists

We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.

Automated summary

The newly designed and synthesized bivalent analogue 27 showed significant increase in cellular activity and caused substantial tumor regressions in MDA-MB-231 xenograft model, indicating its promising potential as an effective anti-tumor agent.