Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt's lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound's therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.

中文翻译：

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OT-82，一种针对血液恶性肿瘤对NAD生物合成的强烈依赖性的新型抗癌药物。

可以通过调节细胞谱系特异性靶标而不是肿瘤特异性靶标来有效治疗某些类型的癌症。我们进行了系统搜索，寻找对造血源细胞有选择性毒性的新型药物。化学文库筛选后进行前导优化，确定了OT-82，这是一种对造血系统恶性肿瘤具有强效作用的小分子，包括体外和小鼠异种移植模型中的急性粒细胞和淋巴母细胞成年和小儿白血病，红细胞白血病，多发性骨髓瘤和Burkitt淋巴瘤。与健康的骨髓造血前体相比，OT-82对患者的白血病细胞毒性更大。OT-82被证明可通过抑制烟酰胺磷酸核糖基转移酶（NAMPT）诱导细胞死亡，NAD合成挽救途径中的限速酶。在小鼠中，OT-82剂量和日粮烟酸的优化进一步扩大了该化合物的治疗指数。在对小鼠和非人类灵长类动物进行的毒理学研究中，OT-82显示，使用其他NAMPT抑制剂未观察到心脏，神经或视网膜毒性，并且对小鼠衰老或寿命没有影响。造血器官和淋巴器官被确定为这两种物种中OT-82剂量限制性毒性的主要靶标。这些结果表明造血起源的赘生性细胞对NAMPT的强烈依赖性，并引入OT-82作为治疗血液恶性肿瘤的有希望的候选者。在对小鼠和非人类灵长类动物进行的毒理学研究中，OT-82表明，使用其他NAMPT抑制剂未观察到心脏，神经或视网膜毒性，并且对小鼠衰老或寿命没有影响。造血器官和淋巴器官被确定为这两种物种中OT-82剂量限制性毒性的主要靶标。这些结果揭示了造血起源的赘生性细胞对NAMPT的强烈依赖性，并引入OT-82作为治疗血液恶性肿瘤的有希望的候选者。在对小鼠和非人类灵长类动物进行的毒理学研究中，OT-82表明，使用其他NAMPT抑制剂未观察到心脏，神经或视网膜毒性，并且对小鼠衰老或寿命没有影响。造血器官和淋巴器官被确定为这两种物种中OT-82剂量限制性毒性的主要靶标。这些结果揭示了造血起源的赘生性细胞对NAMPT的强烈依赖性，并引入OT-82作为治疗血液恶性肿瘤的有希望的候选者。