New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Abstract

Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

“…Taking VEGFR-2 as the target, the search for VEGFR-2 inhibitors provides a good way to find some new anticancer drugs. Based on conserved active binding sites of VEGFR-2 and similar interaction conformation with ligands, several novel inhibitors of VEGFR-2 have been developed [48], in which pyrazolones play important roles as well.…”

FAK is Required for Tumor Metastasis-Related Fluid Microenvironment in Triple-Negative Breast Cancer

“…This effect might sensitize the tumor to radiotherapy and increase its exposure to cytotoxic chemotherapy [10,16,17,18]. Many investigators have studied the biological effects of the combination of anti-angiogenic agents and chemo- or radio-therapy on TNBC [20,21,22]; however, the role of FSS in regulating drug sensitivity and cellular functions in cancer cells is not yet understood.…”

Anlotinib suppresses metastasis and multidrug resistance via dual blockade of MET/ABCB1 in colorectal carcinoma cells

“…Single (bevacizumab and cetuximab) and multiple angiogenesis inhibitors (sorafenib and sunitinib) are used to treat advanced CRC [11,12]. However, antiangiogenic therapy was reported to generate elicitation effect in tumor adaptation and progression of the disease that leads to local invasion and distant metastasis [13][14][15]. In this respect, an agent that could simultaneously suppress vascular endothelial growth factor (VEGF) and other pathways…”