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Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-24 , DOI: 10.1021/acs.jmedchem.3c01819
John S Tyhonas 1 , Lee D Arnold 1 , Jason M Cox 1 , Aleksandra Franovic 1 , Elisabeth Gardiner 1 , Kathryn Grandinetti 1 , Robert Kania 1 , Toufike Kanouni 1 , Matthew Lardy 1 , Chun Li 1 , Eric S Martin 1 , Nichol Miller 1 , Adithi Mohan 1 , Eric A Murphy 1 , Michelle Perez 1 , Liliana Soroceanu 1 , Noel Timple 1 , Sean Uryu 1 , Scott Womble 1 , Stephen W Kaldor 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-24 , DOI: 10.1021/acs.jmedchem.3c01819
John S Tyhonas 1 , Lee D Arnold 1 , Jason M Cox 1 , Aleksandra Franovic 1 , Elisabeth Gardiner 1 , Kathryn Grandinetti 1 , Robert Kania 1 , Toufike Kanouni 1 , Matthew Lardy 1 , Chun Li 1 , Eric S Martin 1 , Nichol Miller 1 , Adithi Mohan 1 , Eric A Murphy 1 , Michelle Perez 1 , Liliana Soroceanu 1 , Noel Timple 1 , Sean Uryu 1 , Scott Womble 1 , Stephen W Kaldor 1
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Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.
中文翻译：
发现 KIN-3248，一种不可逆的下一代 FGFR 抑制剂，用于治疗携带 FGFR2 和/或 FGFR3 基因改变的晚期肿瘤
成纤维细胞生长因子受体（FGFR）改变在多种癌症中作为致癌驱动因素和旁路机制存在。这些改变可以包括融合、扩增、重排和突变。对当前 FGFR 抑制剂的获得性耐药性通常会导致疾病进展并给患者带来不利的结果。临床上对当前 FGFR 抑制剂耐药的肿瘤的基因组分析揭示了一些获得性驱动改变，这些改变可能成为下一代治疗的目标。在此，我们描述了如何使用基于结构的药物设计 (SBDD) 来发现有效的激酶组选择性泛 FGFR 抑制剂KIN-3248 ，该抑制剂对许多获得性耐药突变具有活性。 KIN-3248目前正处于 I 期临床开发阶段，用于治疗携带 FGFR2 和/或 FGFR3 基因改变的晚期肿瘤。
更新日期：2024-01-24
中文翻译：
发现 KIN-3248，一种不可逆的下一代 FGFR 抑制剂，用于治疗携带 FGFR2 和/或 FGFR3 基因改变的晚期肿瘤
成纤维细胞生长因子受体（FGFR）改变在多种癌症中作为致癌驱动因素和旁路机制存在。这些改变可以包括融合、扩增、重排和突变。对当前 FGFR 抑制剂的获得性耐药性通常会导致疾病进展并给患者带来不利的结果。临床上对当前 FGFR 抑制剂耐药的肿瘤的基因组分析揭示了一些获得性驱动改变，这些改变可能成为下一代治疗的目标。在此，我们描述了如何使用基于结构的药物设计 (SBDD) 来发现有效的激酶组选择性泛 FGFR 抑制剂KIN-3248 ，该抑制剂对许多获得性耐药突变具有活性。 KIN-3248目前正处于 I 期临床开发阶段，用于治疗携带 FGFR2 和/或 FGFR3 基因改变的晚期肿瘤。
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