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أ. د. عبدالرحمن بن عبدالعزيز المهيزع Prof. Abdulrahman A. Almehizia

Professor

Professor of Medicinal Chemistry

كلية الصيدلة
كلية الصيدلة (مبنى رقم 23) الدور الثاني مكتب رقم 2 أ 133
publication
Journal Article
2015

Design and activity of AP endonuclease-1 inhibitors

F, Zhiwei . 2015

Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA glycosylases on modified bases and non-enzymatically by hydrolytic depurination/depyrimidination of nucleobases. Many anticancer drugs generate DNA adducts that are processed by base excision repair, and tumor resistance is frequently associated with enhanced APE-1 expression. Accordingly, APE-1 is a potential therapeutic target to treat cancer. Using computational approaches and the high resolution structure of APE-1, we developed a 5-point pharmacophore model for APE-1 small molecule inhibitors. One of the nM APE-1 inhibitors (AJAY-4) that was identified based on this model exhibited an overall median growth inhibition (GI50) of 4.19 μM in the NCI-60 cell line panel. The mechanism of action is shown to be related to the buildup of abasic sites that cause PARP activation and PARP cleavage, and the activation of caspase-3 and caspase-7, which is consistent with cell death by apoptosis. In a drug combination growth inhibition screen conducted in 10 randomly selected NCI-60 cell lines and with 20 clinically used non-genotoxic anticancer drugs, a synergy was flagged in the SK-MEL-5 melanoma cell line exposed to combinations of vemurafenib, which targets melanoma cells with V600E mutated BRAF, and AJAY-4, our most potent APE-1 inhibitor. The synergy between AJAY-4 and vemurafenib was not observed in cell lines expressing wild-type B-Raf protein. This synergistic combination may provide a solution to the resistance that develops in tumors treated with B-Raf-targeting drugs.

Volume Number
8
Issue Number
3
Magazine \ Newspaper
Journal of Chemical Biology
Pages
79-93
more of publication
publications

Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA…

by Zhiwei F, Stanton K, Close D, Wang L, Srinivasan A, Almehizia A, Iyer P, Xie XQ, Johnston P, Gold B
2015
publications

Multiple myeloma (MM) is an uncontrolled differentiation of plasma B cells and the deposits in the bone marrow. MM accounts for 10% of blood cancers and nearly more than 22,000 new cases are…

by Almehizia A, Yang P, Wang L, Xie XQ
2013
publications

Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a…

by Yang P, Wang L, Feng R, Almehizia A, Tong Q, Myint KZ, Ouyang Q, Alqarni M, Xie XQ
2013