BRAF 抑制剂征战中的挑战与机遇：2002 年至 2022 年,ACS Omega

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BRAF 抑制剂征战中的挑战与机遇：2002 年至 2022 年
ACS Omega ( IF 3.7 ) Pub Date : 2023-07-26 , DOI: 10.1021/acsomega.3c00332
Ankit Kumar Singh ₁ , Pankaj Sonawane ₁ , Adarsh Kumar ₁ , Harshwardhan Singh ₁ , Vladislav Naumovich ₂ , Prateek Pathak ₂ , Maria Grishina ₂ , Habibullah Khalilullah ₃ , Mariusz Jaremko ₄ , Abdul-Hamid Emwas ₅ , Amita Verma ₆ , Pradeep Kumar ₁

Affiliation

丝氨酸/苏氨酸蛋白激酶 B-Raf（BRAF；RAF = 快速加速纤维肉瘤）在丝裂原激活蛋白激酶 (MAPK) 信号级联中发挥重要作用。BRAF基因的体细胞突变由Davies等人于2002年首次发现，这是癌症研究的重大突破。随后，发现了三种不同类别的 BRAF 突变体。此类包括 I 类单体突变体（BRAF ^V600）、II 类 BRAF 同二聚体突变体（非 V600）和 III 类 BRAF 异二聚体（非 V600）。由这些引起的癌症包括黑色素瘤、甲状腺癌、卵巢癌、结直肠癌、非小细胞肺癌等。在这项研究中，我们重点介绍了 BRAF 蛋白中的主要结合口袋、它们与抑制剂的活性和非活性构象，以及 BRAF 二聚化及其在矛盾激活和 BRAF 突变中的重要性。我们讨论了美国食品和药物管理局批准的第一代、第二代和第三代药物以及正在进行临床试验的药物，其采用 DFG-IN/OUT 和 αC-IN/OUT 与 BRAF 蛋白的所有四种不同的结合方式。我们研究了所有三代抑制剂的特殊方面和困难。最后，这项研究还涵盖了合成 BRAF 抑制剂的最新进展（从 2002 年的发现到 2022 年）、它们的独特性质以及抑制 BRAF 突变体的重要性。

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Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022

Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF^V600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

更新日期：2023-07-26

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