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Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-05-13 , DOI: 10.1016/j.ccell.2019.04.006 Bryan D Smith 1 , Michael D Kaufman 1 , Wei-Ping Lu 1 , Anu Gupta 1 , Cynthia B Leary 1 , Scott C Wise 1 , Thomas J Rutkoski 1 , Yu Mi Ahn 1 , Gada Al-Ani 1 , Stacie L Bulfer 1 , Timothy M Caldwell 1 , Lawrence Chun 2 , Carol L Ensinger 1 , Molly M Hood 1 , Arin McKinley 3 , William C Patt 1 , Rodrigo Ruiz-Soto 1 , Ying Su 1 , Hanumaiah Telikepalli 1 , Ajia Town 3 , Benjamin A Turner 1 , Lakshminarayana Vogeti 1 , Subha Vogeti 1 , Karen Yates 1 , Filip Janku 4 , Albiruni Ryan Abdul Razak 5 , Oliver Rosen 1 , Michael C Heinrich 3 , Daniel L Flynn 1
Cancer Cell ( IF 48.8 ) Pub Date : 2019-05-13 , DOI: 10.1016/j.ccell.2019.04.006 Bryan D Smith 1 , Michael D Kaufman 1 , Wei-Ping Lu 1 , Anu Gupta 1 , Cynthia B Leary 1 , Scott C Wise 1 , Thomas J Rutkoski 1 , Yu Mi Ahn 1 , Gada Al-Ani 1 , Stacie L Bulfer 1 , Timothy M Caldwell 1 , Lawrence Chun 2 , Carol L Ensinger 1 , Molly M Hood 1 , Arin McKinley 3 , William C Patt 1 , Rodrigo Ruiz-Soto 1 , Ying Su 1 , Hanumaiah Telikepalli 1 , Ajia Town 3 , Benjamin A Turner 1 , Lakshminarayana Vogeti 1 , Subha Vogeti 1 , Karen Yates 1 , Filip Janku 4 , Albiruni Ryan Abdul Razak 5 , Oliver Rosen 1 , Michael C Heinrich 3 , Daniel L Flynn 1
Affiliation
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Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
中文翻译：
Ripretinib (DCC-2618) 是一种开关控制激酶抑制剂，适用于多种致癌和耐药 KIT 和 PDGFRA 变体。
Ripretinib (DCC-2618) 旨在抑制癌症和骨髓增殖性肿瘤中发现的全谱突变 KIT 和 PDGFRA 激酶，特别是胃肠道间质瘤 (GIST)，其中耐药 KIT 突变的异质性是一个主要挑战。 Ripretinib 是一种“开关控制”激酶抑制剂，可迫使激活环（或激活“开关”）进入非活性构象。 Ripretinib 可抑制所有测试的 KIT 和 PDGFRA 突变体，值得注意的是，它是一种 II 型激酶抑制剂，已被证明可广泛抑制 KIT 和 PDGFRA 的激活环突变，此前认为只有 I 型抑制剂才能实现。 Ripretinib 在临床前癌症模型中显示出疗效，初步临床数据提供了概念证明，Ripretinib 可抑制耐药 GIST 患者中的多种 KIT 突变体。
更新日期：2019-05-16
中文翻译：
Ripretinib (DCC-2618) 是一种开关控制激酶抑制剂，适用于多种致癌和耐药 KIT 和 PDGFRA 变体。
Ripretinib (DCC-2618) 旨在抑制癌症和骨髓增殖性肿瘤中发现的全谱突变 KIT 和 PDGFRA 激酶，特别是胃肠道间质瘤 (GIST)，其中耐药 KIT 突变的异质性是一个主要挑战。 Ripretinib 是一种“开关控制”激酶抑制剂，可迫使激活环（或激活“开关”）进入非活性构象。 Ripretinib 可抑制所有测试的 KIT 和 PDGFRA 突变体，值得注意的是，它是一种 II 型激酶抑制剂，已被证明可广泛抑制 KIT 和 PDGFRA 的激活环突变，此前认为只有 I 型抑制剂才能实现。 Ripretinib 在临床前癌症模型中显示出疗效，初步临床数据提供了概念证明，Ripretinib 可抑制耐药 GIST 患者中的多种 KIT 突变体。
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