Rational design and development of novel NAE inhibitors for the treatment of pancreatic cancer

Abstract

Pancreatic cancer remains clinically challenging because of the lack of efficient targeted therapies and high aggressiveness. NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in cancers. Herein, we report the synthesis, optimization, and evaluation of a new series of pyrido[2,3-d]pyrimidin-7(8H)-one derivative as highly selective and efficacious NAE inhibitors, enabling rapid degradation of related substrates and potent inhibition of BxPC-3 cell proliferation. Moreover, western blot assays demonstrated that compound 51 could inhibit NAE activity, resulting in apoptosis in BxPC-3 cells. Furthermore, compound 51 induced cell apoptosis in vitro and inhibited tumor growth in BxPC-3 xenograft models. Our work established that 51 was a highly potent and efficacious NAE inhibitor, representing an effective strategy and great potential as a new targeted therapy for pancreatic cancer. Graphical abstract