Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents

// Md. Maqusood Alam 1, * , Su-Chan Lee 1, * , Yujin Jung 1 , Hye Jeong Yun 1 , Hye-Young Min 1 , Ho Jin Lee 1 , Phuong Chi Pham 1 , Jayoung Moon 1 , Dah In Kwon 1 , Bumhee Lim 1 , Young-Ger Suh 1 , Jeeyeon Lee 1 , Ho-Young Lee 1 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea * These authors have contributed equally to this work Correspondence to: Jeeyeon Lee, e-mail: jyleeut@snu.ac.kr Ho-Young Lee, e-mail: hylee135@snu.ac.kr Keywords: oxadiazinone, insulin-like growth factor 1 receptor, Src, molecular docking analysis, drug resistance Received: July 10, 2015      Accepted: September 24, 2015      Published: October 23, 2015 ABSTRACT The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo ; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents.