lixumistat (IM156)

Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

P1, N=25, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

Sensitivity of HA cells to 2-deoxyglucose, an inhibitor of glycolysis was markedly increased (Figure 1)...Sensitivity of HA cells to a panel of the tested cytotoxic drugs (cytarabin, cisplatin, bortezomib) and targeted agents (venetoclax, S63545, A1155463, TRAIL, polatuzumab vedotin, IM-156, copanlisib) was either unchanged or increased (compared to sensitivity of the original cell lines cultured under normoxia)...In translation, P4HA1, BCL-XL, and structural proteins of the glycolytic pathway may represent novel drugable targets for more effective elimination of hypoxia-adapted lymphoma cells. Financial Support: Ministry of Health of the Czech Republic AZV NU23-03-00172, Grant Agency of the Czech Republic GA23-05377S, and National Institute for Cancer Research (EXCELES) LX22NPO5102.

IM156 is the first PC1 OXPHOS inhibitor to have been successfully tested in patients with cancer with the identification of a RP2D. It was well tolerated at dose levels active in preclinical models, and demonstrated modest clinical activity in an unselected population of patients. Subsequent development will focus on OXPHOS-dependent tumors and in combinations with agents in which OXPHOS metabolism is a mechanism of resistance.