Discovery of Cytotoxic Truncated Vitamin D Derivatives Against Both Bortezomib‐Sensitive and Resistant Multiple Myeloma Phenotypes

Abstract

<title>Abstract</title> Multiple myeloma (MM) is an incurable hematological malignancy with increasing incidence and mortality rates with a worldwide incidence of 160,000 cases per year. The current approved treatments including bortezomib have serious side effects and ultimately develop resistance. Inadequate vitamin D (VD) levels are frequent in MM patients and its supplementation has an antiproliferative effect on different MM phenotypes. However, the risk of hypercalcemia restricts VD application in cancer therapy, hence we pursued truncated VD analogues with anticancer effect accompanied with no calcemic activity. Previously, we have revealed a truncated VD2 C/D rings derivative against cervical cancer, lung cancer and MM. Herein, we generate its SAR study by introducing more derivatives and testing then against different MM cells including bortezomib sensitive and resistant phenotypes. Compound VDF4 exhibited remarkable toxicity against all tested cells with less effect on normal blood cells reflecting its potential high selectivity. VDF-4 IC₅₀ value against KMS-12-PE, KMS-11, and KMS-11/BTZ is 19.1±1.0, 19.8±2.5, and 23.3±1.9 respectively. Notably, KMS-11/BTZ was not sensitive to VD2. Furthermore, it demonstrated moderate activity against other leukemic cells including Jurkat and M8166 cells. Although its mechanism of action is not fully understood, VDF-4 stands out as a promising lead compound that warrants further investigations.