Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
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DOI：
10.1038/s43018-023-00630-y
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发表时间：
2023-09
期刊：
影响因子：
22.7
通讯作者：
Somwar, Romel
中科院分区：
文献类型：
--
作者：
Miyazaki, Isao;Odintsov, Igor;Ishida, Keiji;Lui, Allan J. W.;Kato, Masanori;Suzuki, Tatsuya;Zhang, Tom;Wakayama, Kentaro;Kurth, Renate I.;Cheng, Ryan;Fujita, Hidenori;Delasos, Lukas;Vojnic, Morana;Khodos, Inna;Yamada, Yukari;Ishizawa, Kota;Mattar, Marissa S.;Funabashi, Kaoru;Chang, Qing;Ohkubo, Shuichi;Yano, Wakako;Terada, Ryuichiro;Giuliano, Claudio;Lu, Yue Christine;Bonifacio, Annalisa;Kunte, Siddharth;Davare, Monika A.;Cheng, Emily H.;de Stanchina, Elisa;Lovati, Emanuela;Iwasawa, Yoshikazu;Ladanyi, Marc;Somwar, Romel
RET受体酪氨酸激酶在各种癌症（肺癌、甲状腺癌、结肠癌和胰腺癌等）中通过致癌融合或功能获得性单核苷酸变体被激活。小分子RET激酶抑制剂成为RET驱动的晚期恶性肿瘤的标准治疗。然而，RET抑制剂的治疗益处受到药物靶点中获得性突变以及脑转移的限制，这可能是由于脑渗透不足。在这里，我们对vepafestinib（TAS 0953/HM 06）进行了临床前表征，vepafestinib是一种具有独特结合模式的下一代RET抑制剂。我们证明，vepafestinib对RET具有同类最佳的选择性，同时对常见报告的靶向耐药突变（RETL 730、RETV 804和RETG 810中的变体）发挥活性，并且与目前批准的RET药物相比，在大脑中显示出上级药代动力学特性。我们进一步表明，这些特性转化为改善肿瘤控制在颅内模型的RET驱动的癌症。我们的研究结果强调了vepafestinib在治疗RET驱动的癌症方面的临床潜力。宫崎et al.表征了vepafestinib，一种对野生型RET和溶剂前沿突变体具有选择性的下一代RET抑制剂。由于独特的结合模式，它增强了大脑的兴奋性，并克服了对其他RET抑制剂的耐药性。
RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers. Miyazaki et al. characterize vepafestinib, a next-generation RET inhibitor that is selective for wild-type RET and solvent front mutants. Due to a unique binding mode, it has enhanced brain penetrance and overcomes resistance to other RET inhibitors.
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DOI：
10.1200/jco.22.00393
发表时间：
2023-01-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
通讯作者：
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影响因子：
16.6
作者：
Nakaoku T;Kohno T;Araki M;Niho S;Chauhan R;Knowles PP;Tsuchihara K;Matsumoto S;Shimada Y;Mimaki S;Ishii G;Ichikawa H;Nagatoishi S;Tsumoto K;Okuno Y;Yoh K;McDonald NQ;Goto K
通讯作者：
Goto K
影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N
影响因子：
3.9
作者：
Feng, Bo;Mills, Jessica B.;de Morais, Sonia M.
通讯作者：
de Morais, Sonia M.