CC-90009 是一种新型 Cereblon E3 连接酶调节剂，靶向 GSPT1 降解以诱导针对急性髓性白血病 (AML) 的有效杀肿瘤活性,Blood

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CC-90009 是一种新型 Cereblon E3 连接酶调节剂，靶向 GSPT1 降解以诱导针对急性髓性白血病 (AML) 的有效杀肿瘤活性
Blood ( IF 21.0 ) Pub Date : 2019-11-13 , DOI: 10.1182/blood-2019-127892
Antonia Lopez-Girona ₁ , Gang Lu ₂ , Emily Rychak ₁ , Derek Mendy ₁ , Chin-Chun Lu ₁ , Irit Rappley ₁ , Celia Fontanillo ₁ , Brian E. Cathers ₃ , Thomas O. Daniel ₃ , Joshua Hansen ₁

Affiliation

cereblon E3 连接酶调节剂 (CELMoD) CC-885 与 CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 泛素连接酶复合物共同触发翻译终止因子 G1 到 S 相变 1 (GSPT1) 的泛素化和蛋白酶体降解，导致 AML 细胞系和原发性患者原始细胞的强烈生长抑制 (Matyskiela ME, et al. Nature. 2016;535:252-7)。然而，CC-885 也会引发其他 cereblon (CRBN) 新底物的脱靶降解，可能导致毒性。在这里，我们介绍了一种新型 GSPT1 选择性 CELMoD、CC-90009 的鉴定，以及其在复发性或难治性 (R/R) AML (CC-90009-AML-001; NCT02848001) 中临床开发的机制原理。为了识别新的 CELMoD 代理，我们使用一组含有常见致癌突变的 11 种人类 AML 细胞系进行了基于细胞的表型筛选。筛选确定了 CC-90009，它在 11 个细胞系中的 10 个细胞系中显示出有效的抗增殖和促凋亡活性，50% 抑制浓度 (IC50) 值范围为 3 至 75 nM。5 种 AML 细胞系在暴露于 CC-90009 后 16 至 48 小时达到最大细胞凋亡，细胞在处理后 8-16 小时内发生细胞凋亡。然后在从 30 名新诊断或 R/R AML 患者获得的一组样本中测试 CC-90009。在患者诊断期间获得的骨髓抽吸物在不分离组成细胞的情况下进行铺板，并使用 PharmaFlow PM 测试测试对 CC-90009 的敏感性，据报道该测试可预测对标准护理化疗的临床反应，准确率为 81%（Martínez- Cuadrón D 等人 Leuk Res. 2019;76:1-10)。CC-90009 的疗效在 30 个患者样本中的 26 个中呈浓度依赖性，平均半最大反应浓度 (EC50) 为 21 nM。白血病细胞杀伤迅速且高效：> 82% 的白血病细胞在 24 小时内被清除，几乎全部在 96 小时内被清除。相比之下，CC-90009 在相同的患者样本中对正常淋巴细胞仅表现出适度的活性。通过 CRISPR/Cas9 介导的基因编辑敲除 CRBN 完全消除了敏感 AML 细胞系中 CC-90009 的活性，这表明 CC-90009 的抗 AML 活性是由 GSPT1 的降解介导的。对用 CC-90009 处理的 AML 细胞的串联质谱标签定量质谱分析表明，CC-90009 选择性地降低了 GSPT1 的丰度，而对蛋白质组的其余部分几乎没有影响。CC-90009 对 GSPT1 的降解被 CRL4CRBN E3 泛素连接酶复合物的蛋白酶体抑制或失活所阻断。GSPT1 抗降解突变体 G575N 的过表达赋予对 CC-90009 的完全抗性，而 RNA 干扰 (RNAi) 介导的 GSPT1 基因表达的部分敲低增强了对 CC-90009 的反应。机械地，CC-90009 诱导的 GSPT1 降解触发整合应激反应途径的激活，该途径与诱导细胞凋亡和抑制增殖有关。CC-90009 是一种 CELMoD 和一流的 GSPT1 降解剂，进入临床开发阶段。GSPT1 的降解被证实对于 CC-90009 诱导的细胞凋亡和抗增殖活性是必不可少的。CC-90009 在 > 80% 的人类 AML 细胞系和患者原始细胞中的显着抗增殖活性强烈支持正在进行的 R/R AML 的 1 期研究。披露 Lopez-Girona：Celgene Corporation：就业。Lu:Celgene Corporation：就业、股权。Rychak：Celgene Corporation：就业、股权。Mendy：Celgene Corporation：就业。陆：新基公司：就业，股权。Rappley：Celgene Corporation：就业。Fontanillo：Celgene Corporation：就业。凯瑟斯：全球血液治疗学（GBT）：就业；新基公司：股权。丹尼尔：Celgene Corporation：就业。汉森：Celgene Corporation：就业。

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CC-90009, a Novel Cereblon E3 Ligase Modulator, Targets GSPT1 for Degradation to Induce Potent Tumoricidal Activity Against Acute Myeloid Leukemia (AML)

The cereblon E3 ligase modulator (CELMoD) CC-885 co-opts the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex to trigger the ubiquitination and proteasomal degradation of the translation termination factor G1 to S phase transition 1 (GSPT1), resulting in robust growth inhibition in AML cell lines and primary patient blasts (Matyskiela ME, et al. Nature. 2016;535:252-7). However, CC-885 also triggers off-target degradation of other cereblon (CRBN) neosubstrates, potentially leading to toxicities. Here, we present the identification of a novel GSPT1-selective CELMoD, CC-90009, and the mechanistic rationale for its clinical development in relapsed or refractory (R/R) AML (CC-90009-AML-001; NCT02848001). To identify new CELMoD agents, we performed cell-based phenotypic screening using a panel of 11 human AML cell lines harboring common oncogenic mutations. The screening identified CC-90009, which demonstrated potent antiproliferative and proapoptotic activity with 50% inhibitory concentration (IC50) values ranging from 3 to 75 nM in 10 out of 11 cell lines. Maximal apoptosis was reached between 16 and 48 hours post exposure to CC-90009 in 5 AML cell lines with cells being committed to apoptosis within 8-16 hours of treatment. CC-90009 was then tested in a panel of samples obtained from 30 patients with newly diagnosed or R/R AML. Bone marrow aspirates obtained during patient diagnosis were plated without separation of constituent cells and tested for sensitivity to CC-90009 using the PharmaFlow PM test which was reported to predict clinical response to standard-of-care chemotherapy with 81% accuracy in AML (Martínez-Cuadrón D, et al. Leuk Res. 2019;76:1-10). The efficacy of CC-90009 was concentration dependent in 26 of 30 patient samples, with an average half-maximal response concentration (EC50) of 21 nM. Leukemic cell killing was rapid and highly efficient: > 82% of leukemic cells were eliminated within 24 hours and nearly all were eliminated within 96 hours. In contrast, CC-90009 showed only modest activity against normal lymphocytes in the same patient samples. Knockout of CRBN via CRISPR/Cas9-mediated gene editing completely abrogated the activity of CC-90009 in sensitive AML cell lines, suggesting that the anti-AML activity of CC-90009 is mediated by the degradation of GSPT1. Tandem mass tag quantitative mass spectrometry analysis of AML cells treated with CC-90009 revealed that CC-90009 selectively reduced the abundance of GSPT1 with little to no effect on the rest of the proteome. The degradation of GSPT1 by CC-90009 was blocked by proteasomal inhibition or inactivation of the CRL4CRBN E3 ubiquitinligase complex. Overexpression of a GSPT1-degradation-resistant mutant, G575N, conferred complete resistance to CC-90009, while RNA interference (RNAi)-mediated partial knockdown of GSPT1 gene expression enhanced the response to CC-90009. Mechanistically, GSPT1 degradation induced by CC-90009 triggers the activation of the integrated stress response pathway, which is associated with the induction of apoptosis and inhibition of proliferation. CC-90009 is a CELMoD and first-in-class GSPT1 degrader entering clinical development. The degradation of GSPT1 was confirmed to be essential for CC-90009-induced apoptosis and antiproliferative activity. The profound antiproliferative activity of CC-90009 in > 80% of human AML cell lines and patient blasts strongly supports the ongoing phase 1 study in R/R AML. Disclosures Lopez-Girona: Celgene Corporation: Employment. Lu:Celgene Corporation: Employment, Equity Ownership. Rychak:Celgene Corporation: Employment, Equity Ownership. Mendy:Celgene Corporation: Employment. Lu:Celgene Corporation: Employment, Equity Ownership. Rappley:Celgene Corporation: Employment. Fontanillo:Celgene Corporation: Employment. Cathers:Global Blood Therapeutics (GBT): Employment; Celgene Corporation: Equity Ownership. Daniel:Celgene Corporation: Employment. Hansen:Celgene Corporation: Employment.

更新日期：2019-11-13

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