Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer

Aisha A K Al-Ashmawy; Khaled M Elokely; Oscar Perez-Leal; Mario Rico; John Gordon; George Mateo; Abdelsattar M Omar; Magid Abou-Gharbia; Wayne E Childers Jr

doi:10.1021/acsmedchemlett.0c00289

Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer

ACS Med Chem Lett. 2020 Oct 12;11(11):2156-2164. doi: 10.1021/acsmedchemlett.0c00289. eCollection 2020 Nov 12.

Authors

Aisha A K Al-Ashmawy^{1

2}, Khaled M Elokely^{1

3

4}, Oscar Perez-Leal¹, Mario Rico¹, John Gordon¹, George Mateo¹, Abdelsattar M Omar^{5

6}, Magid Abou-Gharbia¹, Wayne E Childers Jr¹

Affiliations

¹ Moulder Center for Drug Discovery Research, Temple University, School of Pharmacy, 3307 N. Broad Street, Philadelphia, Pennsylvania 19140, United States.
² Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Division, National Research Center, Dokki, Cairo 12622, Egypt.
³ Department of Pharmaceutical Chemistry, Tanta University, Tanta 31527, Egypt.
⁴ Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201, United States.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.

Abstract

The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC₅₀ values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.