精氨酸酶 1/2 抑制剂 OATD-02：从发现到首次用于癌症免疫治疗,Molecular Cancer Therapeutics

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精氨酸酶 1/2 抑制剂 OATD-02：从发现到首次用于癌症免疫治疗
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2023-03-20 , DOI: 10.1158/1535-7163.mct-22-0721
Bartlomiej Borek ₁ , Julita Nowicka ₁ , Anna Gzik ₁ , Marek Dziegielewski ₁ , Karol Jedrzejczak ₁ , Joanna Brzezinska ₁ , Marcin Grzybowski ₁ , Paulina Stanczak ₁ , Paulina Pomper ₁ , Agnieszka Zagozdzon ₁ , Tomasz Rejczak ₁ , Krzysztof Matyszewski ₁ , Adam Golebiowski ₁ , Jacek Olczak ₁ , Kamil Lisiecki ₁ , Magdalena Tyszkiewicz ₁ , Magdalena Kania ₁ , Sylwia Piasecka ₁ , Anna Cabaj ₁ , Paulina Dera ₁ , Krzysztof Mulewski ₁ , Jacek Chrzanowski ₁ , Damian Kusmirek ₁ , Elzbieta Sobolewska ₁ , Marta Magdycz ₁ , Lukasz Mucha ₁ , Marek Masnyk ₁ , Jakub Golab ₂ , Marcin Nowotny ₃ , Elzbieta Nowak ₃ , Agnieszka Napiorkowska-Gromadzka ₃ , Stanislaw Pikul ₁ , Radoslaw Jazwiec ₄ , Karolina Dzwonek ₁ , Pawel Dobrzanski ₁ , Michael Meyring ₅ , Krzysztof Skowronek ₆ , Piotr Iwanowski ₁ , Zbigniew Zaslona ₁ , Roman Blaszczyk ₁

Affiliation

药物抑制控制免疫途径的酶精氨酸酶 1 和 2（ARG1 和 ARG2）是一种有前景的癌症免疫治疗策略。在此，我们报告了 OATD-02 的发现和开发，这是一种口服生物可利用的强效精氨酸酶抑制剂。OATD-02独特的药理学特性通过靶向细胞内ARG1和ARG2以及药物靶标停留时间长、中等到高分布体积和低清除率得到证明，这些特性可能共同提供对抗精氨酸酶相关肿瘤免疫抑制的武器和ARG2依赖性肿瘤细胞生长。OATD-02单一疗法在多种肿瘤模型中具有抗肿瘤作用，并增强了其他免疫调节剂的疗效。已完成的非临床研究和人体药代动力学预测表明了可行的治疗窗口，并允许为癌症患者的首次人体临床研究提出剂量范围。意义：我们开发了一种口服的小分子细胞内精氨酸酶 1 和 2 抑制剂，作为癌症免疫治疗的潜在增强剂。由于非临床研究显示其良好的药理学特性，OATD-02 消除了两种精氨酸酶诱导的肿瘤免疫抑制，使其成为进入临床试验的有前途的候选药物。

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Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer. Significance: We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.

更新日期：2023-03-20

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