Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment

• Main Authors: Sreenivasulu Godesi (Author), Jeong-Ran Han (Author), Jang-Keun Kim (Author), Dong-Ik Kwak (Author), Joohan Lee (Author), Hossam Nada (Author), Minkyoung Kim (Author), Hyun-A Yang (Author), Joo-Young Im (Author), Hyun Seung Ban (Author), Chang Hoon Lee (Author), Yongseok Choi (Author), Misun Won (Author), Kyeong Lee (Author)
• Format: Book
• Published: MDPI AG, 2023-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph16050683; 1424-8247
• Keywords: MDH1/2; inhibitors; HIF-1α; lung cancer; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 16, Iss 5, p 683 (2023)

MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound <b>50</b> containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with <b>LW1497</b>. Compound <b>50</b> reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as <i>GLUT1</i> and pyruvate dehydrogenase kinase 1 (<i>PDK1)</i> in a dose-dependent manner. Furthermore, compound <b>50</b> inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound <b>50</b> may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.