Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg¹³². Having identified an allosteric, induced pocket of IDH1^R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

中文翻译：

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脑渗透突变IDH1抑制剂临床候选IDH305的发现和评估。

突变IDH1的抑制作用正在临床上评估为Arg ¹³²处具有热点突变的各种癌症的有前途的治疗选择。确定了IDH1 ^R132H的变构，诱导口袋后，我们探索了3-嘧啶-4-基-恶唑烷-2-酮作为IDH1突变体抑制剂，用于体内调节2-HG的产生和潜在的脑渗透。我们在这里报告优化工作，以鉴定临床候选者IDH305（13），这是一种有效且选择性的突变体IDH1抑制剂，已在啮齿动物中证明了其对大脑的暴露。该化合物在临床上的临床前表征患者体内IDH1突变异种移植肿瘤模型中2-HG降低与疗效的相关性。IDH305（13）已进入用于治疗具有IDH1突变的癌症的人类临床试验。