Benton Thomas Z, Mills Catherine M, Turner Jonathan M, Francis Megan J, Solomon Dalan J, Burger Pieter B, Peterson Yuri K, Dolloff Nathan G, Bachmann André S, Woster Patrick M
Dept. of Drug Discovery and Biomedical Sciences, Medical University of South Carolina 70 President St Charleston SC 29425 USA
Dept of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina 173 Ashley Ave. Charleston SC 29425 USA.
RSC Adv. 2021 Oct 11;11(53):33260-33270. doi: 10.1039/d1ra06266b. eCollection 2021 Oct 8.
The ectoenzyme CD38 is highly expressed on the surface of mature immune cells, where they are a marker for cell activation, and also on the surface of multiple tumor cells such as multiple myeloma (MM). CD38-targeted monoclonal antibodies (MABs) such as daratumumab and isatuximab bind to CD38 and promote cancer cell death by stimulating the antitumor immune response. Although MABs are achieving unprecedented success in a percentage of cases, high rates of resistance limit their efficacy. Formation of the immunosuppressive intermediate adenosine is a major route by which this resistance is mediated. Thus there is an urgent need for small molecule agents that boost the immune response in T-cells. Importantly, CD38 is a dual-function enzyme, serving as a hydrolase and a nicotinamide adenine dinucleotide (NAD) cyclase, and both of these activities promote immunosuppression. We have employed virtual and physical screening to identify novel compounds that are selective for either the hydrolase or the cyclase activity of CD38, and have demonstrated that these compounds activate T cells . We are currently optimizing these inhibitors for use in immunotherapy. These small molecule inhibitors of the CD38-hydrolase or cyclase activity can serve as chemical probes to determine the mechanism by which CD38 promotes resistance to MAB therapy, and could become novel and effective therapeutic agents that produce immunostimulatory effects. Our studies have identified the first small molecule inhibitors of CD38 specifically for use as immunostimulants.
胞外酶CD38在成熟免疫细胞表面高度表达，是细胞活化的标志物，在多发性骨髓瘤（MM）等多种肿瘤细胞表面也有表达。达雷妥尤单抗和isatuximab等靶向CD38的单克隆抗体（MABs）与CD38结合，通过刺激抗肿瘤免疫反应促进癌细胞死亡。尽管MABs在一定比例的病例中取得了前所未有的成功，但高耐药率限制了它们的疗效。免疫抑制中间体腺苷的形成是介导这种耐药性的主要途径。因此，迫切需要能增强T细胞免疫反应的小分子药物。重要的是，CD38是一种双功能酶，作为水解酶和烟酰胺腺嘌呤二核苷酸（NAD）环化酶，这两种活性都促进免疫抑制。我们利用虚拟筛选和实体筛选来鉴定对CD38的水解酶或环化酶活性具有选择性的新型化合物，并证明这些化合物可激活T细胞。我们目前正在优化这些抑制剂以用于免疫治疗。这些抑制CD38水解酶或环化酶活性的小分子抑制剂可作为化学探针来确定CD38促进对MAB治疗耐药的机制，并可能成为产生免疫刺激作用的新型有效治疗药物。我们的研究确定了首批专门用作免疫刺激剂的CD38小分子抑制剂。
