2. Academic Validation
  3. A bioisosteric approach to the discovery of novel N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide-based activators of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation

A bioisosteric approach to the discovery of novel N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide-based activators of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation

  • Eur J Med Chem. 2022 Sep 5;239:114501. doi: 10.1016/j.ejmech.2022.114501.
Jinsook Kwak 1,  Min-Jung Kim 2,  Soyeong Kim 3,  Ga-Bin Park 2,  Jeyun Jo 1,  Myeonggyo Jeong 1,  Seongeun Kang 3,  Sungwon Moon 1,  Seorin Bang 1,  Hongchan An 4,  Seonghwan Hwang 1,  Min-Soo Kim 1,  Jin-Wook Yoo 1,  Hyung Ryong Moon 1,  Woochul Chang 5,  Ki Wung Chung 1,  Jee-Yeong Jeong 6,  Hwayoung Yun 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
  • 2 Department of Biochemistry, Kosin University College of Medicine, Busan, 49267, Republic of Korea.
  • 3 College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 4 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 5 Department of Biology Education, College of Education, Pusan National University, Busan, 46241, Republic of Korea.
  • 6 Department of Biochemistry, Kosin University College of Medicine, Busan, 49267, Republic of Korea. Electronic address: jyjeong@kosin.ac.kr.
  • 7 College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea. Electronic address: hyun@pusan.ac.kr.
PMID: 35716517 DOI: 10.1016/j.ejmech.2022.114501
Abstract

Inhibition of translation initiation has emerging implications for the development of mechanism-based Anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1, a novel series of N-aryl-N'-[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure-activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable Anticancer activity. The most promising analogues 19 and 40 possessed higher Cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP.

Keywords

Anticancer activity; Bioisostere; Eukaryotic initiation factor 2α (eIF2α); N-Aryl-N′-[4-(aryloxy)cyclohexyl]squaramide; Structure–activity relationship (SAR).

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