Research Papers:

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

Maqusood Md. Alam, Su-Chan Lee, Yujin Jung, Hye Jeong Yun, Hye-Young Min, Ho Jin Lee, Phuong Chi Pham, Jayoung Moon, Dah In Kwon, Bumhee Lim, Young-Ger Suh, Jeeyeon Lee _ and Ho-Young Lee

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Oncotarget. 2015; 6:40598-40610. https://doi.org/10.18632/oncotarget.5839

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Md. Maqusood Alam1,*, Su-Chan Lee1,*, Yujin Jung1, Hye Jeong Yun1, Hye-Young Min1, Ho Jin Lee1, Phuong Chi Pham1, Jayoung Moon1, Dah In Kwon1, Bumhee Lim1, Young-Ger Suh1, Jeeyeon Lee1, Ho-Young Lee1

1College 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: [email protected]

Ho-Young Lee, e-mail: [email protected]

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


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.

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