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Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-02 , DOI: 10.1021/acs.jmedchem.2c00267 Robin A Fairhurst 1 , Pascal Furet 1 , Patricia Imbach-Weese 1 , Frédéric Stauffer 1 , Heinrich Rueeger 1 , Clive McCarthy 1 , Sebastien Ripoche 1 , Susanne Oswald 1 , Bertrand Arnaud 1 , Aline Jary 1 , Michel Maira 1 , Christian Schnell 1 , Daniel A Guthy 1 , Markus Wartmann 1 , Michael Kiffe 1 , Sandrine Desrayaud 1 , Francesca Blasco 1 , Toni Widmer 1 , Frank Seiler 1 , Sascha Gutmann 1 , Mark Knapp 2 , Giorgio Caravatti 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-02 , DOI: 10.1021/acs.jmedchem.2c00267 Robin A Fairhurst 1 , Pascal Furet 1 , Patricia Imbach-Weese 1 , Frédéric Stauffer 1 , Heinrich Rueeger 1 , Clive McCarthy 1 , Sebastien Ripoche 1 , Susanne Oswald 1 , Bertrand Arnaud 1 , Aline Jary 1 , Michel Maira 1 , Christian Schnell 1 , Daniel A Guthy 1 , Markus Wartmann 1 , Michael Kiffe 1 , Sandrine Desrayaud 1 , Francesca Blasco 1 , Toni Widmer 1 , Frank Seiler 1 , Sascha Gutmann 1 , Mark Knapp 2 , Giorgio Caravatti 1
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Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.
中文翻译：
将 NVP-CLR457 鉴定为口服生物可利用的非 CNS 渗透泛 IA 类磷酸肌醇-3-激酶抑制剂
平衡的泛 I 类磷酸肌醇 3-激酶抑制作为癌症治疗的一种方法，提供了治疗多种肿瘤类型的前景和/或一种使用单一抑制剂实现更高疗效的方法。以 buparlisib 为起点，平衡的泛 I 类 PI3K 抑制剂40 (NVP-CLR457) 被认为是同类最佳的。实现这一特性的优化关键是消除稳定脱靶活性的微管，平衡泛 I 类 PI3K 抑制特性，最大限度地减少 CNS 渗透，以及开发无定形固体分散体配方。讨论了临床研究中40的耐受性差的原因。
更新日期：2022-05-02
中文翻译：
将 NVP-CLR457 鉴定为口服生物可利用的非 CNS 渗透泛 IA 类磷酸肌醇-3-激酶抑制剂
平衡的泛 I 类磷酸肌醇 3-激酶抑制作为癌症治疗的一种方法，提供了治疗多种肿瘤类型的前景和/或一种使用单一抑制剂实现更高疗效的方法。以 buparlisib 为起点，平衡的泛 I 类 PI3K 抑制剂40 (NVP-CLR457) 被认为是同类最佳的。实现这一特性的优化关键是消除稳定脱靶活性的微管，平衡泛 I 类 PI3K 抑制特性，最大限度地减少 CNS 渗透，以及开发无定形固体分散体配方。讨论了临床研究中40的耐受性差的原因。
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