Newly discovered angiogenesis inhibitors and their mechanisms of action

Abstract

In the past decade, the success of angiogenesis inhibitors in clinical contexts has established the antiangiogenic strategy as an important part of cancer therapy. During that time period, we have discovered and reported 17 compounds that exert potent inhibition on angiogenesis. These compounds exhibit tremendous diversity in their sources, structures, targets and mechanisms. These studies have generated new models for further modification and optimization of inhibitory compounds, new information for mechanistic studies and a new drug candidate for clinical development. In particular, through studies on the antiangiogenic mechanism of pseudolaric acid B, we discovered a novel mechanism by which the stability of hypoxia-inducible factor 1α is regulated by the transcription factor c-Jun. We also completed a preclinical study of AL3810, a compound with the potential to circumvent tumor drug resistance to a certain extent. All of these findings will be briefly reviewed in this article.

MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

“…All the lines of evidence suggest that the depolymerization of microtubules is an essential factor for JNK activation. JNK has multiple substrates and is involved in extensive physiologic and pathophysiologic processes and therapeutic responses (8,10,(39)(40)(41). Apparently, it is deserved to put continuous efforts into demonstrating which unknown factor(s) and how they mediate JNK activation.…”

A Systematic Review of the Immune-Regulating and Anticancer Activities of Pseudolaric Acid B

“…It's evident that PAB could down-regulate the levels of mRNA and protein expression of HIF-1α (Liu et al, 2012; Miao et al, 2012; Yu et al, 2012; Wang et al, 2017). Li et al discovered that it occurred because PAB induced the proteasome-executed degradation of the HIF-1α protein (Li et al, 2004).…”

Marine-Derived Angiogenesis Inhibitors for Cancer Therapy

“…Numerous TKs such as VEGFR, EGFR, PDGFR and FGFR play critical roles in tumor angiogenesis, which are the major target (s) of most small-molecule angiogenesis inhibitors in the clinic including sorafenib and sunitinib [7]. As yet, however, only 11 TK-targeted marine-derived angiogenesis inhibitors have been reported, not so many as expected.…”

“…, vascular endothelial growth factor (VEGFR)-related kinases [2], matrix metalloproteinases (MMPs) [3], methionine aminopeptidase (MetAP) [4], actin, microtubule [5], and histone deacetylases (HDACs) [6]. Using small molecules that inhibit angiogenesis-associated proteins has become a successful strategy for cancer therapy in the clinic [7]. …”