Drug Resistance Can be Overcome in Multiple Myeloma and Acute Myeloid Leukemia By Targeting Mcl-1 with the Small Chemical KS18

Abstract

Drug resistance and patient recurrence are still key clinical difficulties in multiple myeloma (MM) treatment, despite the tremendous improvements provided by bortezomib therapy. In many cancers, Mcl-1, a member of the Bcl-2 protein family, helps keep cells alive by preventing their natural death process, apoptosis. The anti-cancer therapeutic promise of Mcl-1 inhibitors is highlighted by the fact that Mcl-1 overexpression increases carcinogenesis and medication resistance. Here, we provide KS18, a powerful pyoluteorin derivative with excellent effectiveness towards Mcl-1-dependent cancer cells, to address this unmet therapeutic need. Based on our results, we conclude that KS18 causes apoptosis in cancer cells through activating the mitochondrial outer membrane permeabilization (MOMP) pathway, with the participation of Bak and Bax, in particular in MM and acute myeloid leukemia (AML). With IC 50 values below 1.5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. Total apoptosis in MM patient samples treated with KS18 was an impressive 88.8 percent. After four weeks of treatment with a single tolerable dose each week, a model of bortezomib-resistant MM showed considerable tumor shrinkage, demonstrating the powerful anti-tumor efficacy of KS18. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical.