Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors,Journal of Medicinal Chemistry

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Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-18 , DOI: 10.1021/acs.jmedchem.4c01288
Simon C C Lucas ₁ , J Henry Blackwell ₁ , Ulf Börjesson ₂ , David Hargreaves ₃ , Alexander G Milbradt ₃ , Mark J Bostock ₃ , Samiyah Ahmed ₄ , Kevin Beaumont ₅ , Tony Cheung ₆ , Sylvain Demanze ₇ , Andrea Gohlke ₃ , Carine Guerot ₇ , Afreen Haider ₃ , Vasudev Kantae ₃ , Gregory W Kauffman ₈ , Olaf Kinzel ₉ , Lea Kupcova ₃ , Michael D Lainchbury ₁ , Michelle L Lamb ₈ , Leonardo Leon ₆ , Adeline Palisse ₉ , Claudia Sacchetto ₁₀ , R Ian Storer ₁ , Nancy Su ₁₁ , Clare Thomson ₇ , John Vales ₃ , Yunhua Chen ₁₂ , Xiaolong Hu ₁₂

Affiliation

Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
DMPK, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Oncology Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Medicinal Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Medicinal Chemistry, Oncology R&D, Acerta B.V., a Member of the AstraZeneca Group, Oss 5349, The Netherlands.
Bioscience, Oncology R&D, Acerta B.V., a Member of the AstraZeneca Group, Oss 5349, The Netherlands.
Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China.

Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a k_inact/K_I of 4600 M^–1 s^–1, shows <1 μM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.

中文翻译：

一系列共价细胞活性 Bfl-1 抑制剂的基于结构优化

Bfl-1 是 Bcl-2 蛋白家族的一员，在细胞凋亡调节中起关键作用，与癌细胞存活和对维奈托克治疗的耐药性有关。由于 BH3 结合位点中独特的半胱氨酸残基，靶向 Bfl-1 的共价抑制剂的开发代表了一种很有前途的癌症治疗策略。在此，描述了使用基于结构的设计从铅样命中优化共价细胞工具。在可逆 X 射线片段筛选的信息下，与关键谷氨酸残基（Glu78）建立相互作用并优化在隐蔽口袋中的结合的策略导致生化效力提高了 1000 倍，而不会增加弹头的反应性。化合物 （R，R，S）-26 的 k_inact/K 为 4600 M^–1 s^–1，在细胞测定和细胞靶标结合中显示 <1 μM 半胱天冬酶激活，并且具有良好的理化性质和有前途的体内特征。

更新日期：2024-09-18

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