Identification of 3-aryl-5-methyl-isoxazole-4-carboxamide derivatives and analogs as novel HIF-2α agonists through docking-based virtual screening and structural modification

Article

Author: Liu, Yao ; Xu, Lei ; Qi, Chengcheng ; Yu, Yanzhen ; Hou, Tingjun ; Chen, Siyuan ; Wang, Zhe ; Sheng, Rong

Hypoxia-inducible factor-2 (HIF-2) serves as the pivotal transcription factor in cellular responses to low oxygen levels, particularly concerning the regulation of erythropoietin (EPO) production. A docking-based virtual screening on crystal structures of HIF-2α inhibitors unexpectedly identified 3-phenyl-5-methyl-isoxazole-4-carboxamide derivative v19 as a hit of HIF-2α agonist. Further structural optimizations of compound v19 led to the discovery of a series of HIF-2α agonists with novel scaffolds. The most promising compounds 12g and 14d exhibited potent HIF-2α agonistic activities in vitro with EC₅₀ values of 2.29 μM and 1.78 μM, respectively. Molecular dynamics simulations have revealed their capacity to allosterically enhance HIF-2 dimerization, which shed light on their mechanism of action. Moreover, compound 14d demonstrated a favorable pharmacokinetic (PK) profile, boasting an impressive oral bioavailability value of 68.71 %. These findings strongly suggest that compound 14d is an auspicious lead compound for the treatment of renal anemia.

11 Nov 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact

Q1 · MEDICINE

Article

Author: Kwon, Ho Jeong ; Kim, Yonghyo ; Cho, Sung Min ; Ko, Minjeong ; Marko-Varga, Gyorgy ; Jung, Yooju

A novel natural small molecule, voacangine (Voa), has been discovered as a potent antiangiogenic compound. Notably, Voa directly binds the kinase domain of the vascular endothelial growth factor receptor 2 (VEGFR2) and thereby inhibits downstream signaling. Herein, we developed synthetic small molecules based on the unique chemical structure of Voa that directly and specifically target and modulate the kinase activity of VEGFR2. Among these Voa structure analogues, Voa analogue 19 (V19) exhibited increased antiangiogenic potency against VEGF-induced VEGFR2 phosphorylation without cytotoxic effects. Moreover, treatment with V19 resulted in significant tumor cell death in a mouse xenograft model. In conclusion, this new VEGFR2 modulator, inspired from the rigid scaffold of a natural compound, Voa, is presented as a potent candidate in the development of new antiangiogenic agents.

01 Nov 2016·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Synthesis and biological evaluation of novel hydrogen sulfide releasing glycyrrhetic acid derivatives

Q2 · MEDICINE

ArticleOA

Author: Song, Heng ; Sun, Yinxing ; Hou, Bingbo ; Xu, Guanglin ; Ao, Guizhen

A series of hybrids, which are composed of glycyrrhetic acid (GA) and slowly hydrogen sulfide-releasing donor ADT-OH, were designed and synthesized to develop anticancer and anti-inflammatory agents. Most of the compounds, whose inhibitory rates were comparable to or higher than those of GA and aspirin, respectively, significantly inhibited xylene-induced ear edema in mice. Especially, compound V4 exhibited the most potent inhibitory rate of 60.7%. Furthermore, preliminary structure-activity relationship studies demonstrated that 3-substituted GA derivatives had stronger anti-inflammatory activities than the corresponding 3-unsubstituted GA derivatives. In addition, anti-proliferative activities of compounds V1-9 were evaluated in three different human cancer cell lines. Compound V4 showed the most high potency against all three tumor cell lines with IC50 values ranging from 10.01 μM in Hep G2 cells to 17.8 μM in MDA-MB-231 cells, which were superior to positive GA.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	US	-	-
Thrombosis	Phase 1	-	Inflazyme Pharmaceuticals	-

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