Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation.
Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation.
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DOI：
10.1039/d1ra06266b
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发表时间：
2021-10-08
期刊：
影响因子：
3.9
通讯作者：
Woster, Patrick M.
中科院分区：
文献类型：
--
作者：
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, Andre S.;Woster, Patrick M.
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，也在多发性骨髓瘤(MM)等多种肿瘤细胞表面表达。CD38靶向的单抗(MAB)，如daratumumab和isatuximab，与CD38结合，通过刺激抗肿瘤免疫反应促进癌细胞死亡。尽管MAB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，迫切需要小分子制剂来增强T细胞的免疫反应。重要的是，CD38是一种双功能酶，既是一种水解酶，又是一种烟酰胺腺嘌呤二核苷酸(NAD+)环化酶，这两种活性都能促进免疫抑制。我们利用虚拟和物理筛选来鉴定对CD38的水解酶或环化酶活性具有选择性的新化合物，并证明这些化合物在体外可以激活T细胞。我们目前正在优化这些抑制剂，用于免疫治疗。这些CD38-水解酶或环化酶活性的小分子抑制剂可以作为化学探针来确定CD38促进MAB治疗抵抗的机制，并可能成为产生免疫刺激作用的新型有效的治疗药物。我们的研究已经确定了CD38的第一个小分子抑制剂，专门用于免疫刺激。化合物1和12为胞外酶的水解酶或环化酶选择性抑制剂，其IC50值分别为4.0和20.8 mM。这两种化合物在体外都能促进细胞内NAD+水平和干扰素γ的增加。
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 in vitro. 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. Compounds 1 and 12 were identified as hydrolase- or cyclase-selective inhibitors of the ectoenzyme with IC50 values of 4.0 and 20.8 mM, respectively. Both compounds promoted increases in cellular NAD+ levels and interferon γ in vitro.
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