<br>用 CD38 小分子抑制剂刺激自然杀伤细胞治疗神经母细胞瘤,Chemical Science

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用 CD38 小分子抑制剂刺激自然杀伤细胞治疗神经母细胞瘤
Chemical Science ( IF 7.6 ) Pub Date : 2023-01-30 , DOI: 10.1039/d2sc05749b
Catherine M Mills ₁ , Thomas Z Benton ₁ , Ivett Piña ₁ , Megan J Francis ₁ , Leticia Reyes ₂ , Nathan G Dolloff ₂ , Yuri K Peterson ₁ , Patrick M Woster ₁

Affiliation

高危神经母细胞瘤 (NB) 占所有儿童癌症死亡人数的 15%。高危 NB 患者的难治性疾病归因于化疗耐药和免疫治疗失败。高危 NB 患者的不良预后表明，开发新的、更有效的治疗方法的医疗需求尚未得到满足。 CD38 是一种免疫调节蛋白，在肿瘤微环境 (TME) 中的自然杀伤 (NK) 细胞和其他免疫细胞上组成型表达。此外，CD38 过度表达与 TME 内免疫抑制环境的传播有关。通过虚拟和物理筛选，我们鉴定出了具有低微摩尔IC ₅₀值的药物样CD38小分子抑制剂。我们已经开始通过对最有效的命中分子进行衍生化来探索 CD38 抑制的结构活性关系，以开发具有类铅理化特性和改进效力的新化合物。我们已经证明，我们的衍生抑制剂化合物2通过将多个供体中的细胞活力提高 190 ± 36% 并显着增加干扰素 γ 来在 NK 细胞中引发免疫调节作用。此外，我们还表明，当给予我们的抑制剂和免疫细胞因子 ch14.18-IL2 联合治疗时，NK 细胞对 NB 细胞表现出增强的细胞毒性（90 分钟内 NB 细胞减少 14%）。在此，我们描述了小分子 CD38 抑制剂的合成和生物学评价，并证明了它们作为 NB 免疫治疗新方法的潜在用途。这些化合物代表了刺激免疫功能以治疗癌症的小分子的第一个例子。

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Stimulation of natural killer cells with small molecule inhibitors of CD38 for the treatment of neuroblastoma

High-risk neuroblastoma (NB) accounts for 15% of all pediatric cancer deaths. Refractory disease for high-risk NB patients is attributed to chemotherapy resistance and immunotherapy failure. The poor prognosis for high-risk NB patients demonstrates an unmet medical need for the development of new, more efficacious therapeutics. CD38 is an immunomodulating protein that is expressed constitutively on natural killer (NK) cells and other immune cells in the tumor microenvironment (TME). Furthermore, CD38 over expression is implicated in propagating an immunosuppressive milieu within the TME. Through virtual and physical screening, we have identified drug-like small molecule inhibitors of CD38 with low micromolar IC₅₀ values. We have begun to explore structure activity relationships for CD38 inhibition through derivatization of our most effective hit molecule to develop a new compound with lead-like physicochemical properties and improved potency. We have demonstrated that our derivatized inhibitor, compound 2, elicits immunomodulatory effects in NK cells by increasing cell viability by 190 ± 36% in multiple donors and by significantly increasing interferon gamma. Additionally, we have illustrated that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. Herein we describe the synthesis and biological evaluation of small molecule CD38 inhibitors and demonstrate their potential utility as a novel approach to NB immunotherapy. These compounds represent the first examples of small molecules that stimulate immune function for the treatment of cancer.

更新日期：2023-01-30

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