Discovery of a New Series of Naphthamides as Potent VEGFR-2 Kinase Inhibitors

Abstract

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a new series of naphthamides as potent inhibitors of VEGFR-2. Among these compounds, 14c exhibited high VEGFR-2 inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with IC 50 values of 1.5 and 0.9 nM, respectively. Kinase selectivity profiling revealed that 14c was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-β, and RET. Furthermore, 14c effectively blocked tube formation of HUVEC at nanomolar level. Overall, 14c might be a promising candidate for the treatment of cancer.

Discovery of 1,3‐Diaryl‐pyridones as Potent VEGFR‐2 Inhibitors: Design, Synthesis, and Biological Evaluation

“…In both series, one of the NHs in the urea moiety is cyclized with the middle phenyl ring either to form naphthamides or to form 2,3-dihydro-4H-benzo [b] [1,4]oxazine-4-carboxamides while maintaining the potency (IC 50 values of 0.5 nM for compounds 1 and 2) (Figure 1, cyclization pattern 1). This phenomenon was also found to be consistent with our previous study (27). In view of these facts, we envisioned that cyclization of the urea moiety to form pyridones (Figure 1, cyclization pattern 2) would also be acceptable.…”

Cytotoxic, Apoptosis-Inducing Activities, and Molecular Docking of a New Sterol from Bamboo Shoot Skin Phyllostachys heterocycla var. pubescens

“…Tyrosine-specific protein kinase (TPK) is overexpressed in solid tumors and initiate its proliferation, so the escalation of drugs inhibiting TPK contributes as a significant insight in cancer treatment. The blocking of the vascular endothelial growth factor receptor (VEGFR-2) signaling pathway has become an appealing approach in the therapy of different cancer types [16]. Accordingly, TPK and VEGFR-2 are chosen as the biological targets for implementing the docking studies for the pure isolated compounds.…”

Discovery of anilinopyrimidine-based naphthamide derivatives as potent VEGFR-2 inhibitors

“…In this paper, we report the design, synthesis, and structure-activity relationships (SAR) of a new series of naphthamide derivatives as potent VEGFR-2 inhibitors. 20 In an attempt to discover new scaffolds for VEGFR-2 inhibitors, we compared the binding modes of 1 and 2 with VEGFR-2. With the pyrimidine N-1 and C-2 anilino NH forming two hydrogen bonds with the backbone of Cys919， compound 1 binds to the ATP binding site of VEGFR-2.…”

“…19 We have previously reported a series of heterocyclesubstituted naphthamides as potent VEGFR-2 inhibitors. 20 In an attempt to discover new scaffolds for VEGFR-2 inhibitors, we compared the binding modes of 1 and 2 with VEGFR-2. As illustrated in Fig.…”