Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.

IF 11.5 Q1 HEMATOLOGY
Pramod C Nair, Jacob Piehler, Denis Tvorogov, David M Ross, Angel F Lopez, Jason Gotlib, Daniel Thomas
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引用次数: 0

Abstract

Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN); however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable.

Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.

用于治疗骨髓增生性肿瘤的下一代JAK2抑制剂:基于结构的药物发现方法的经验教训。
自从发现骨髓增生性肿瘤(MPN)患者中存在JAK2 V617F突变以来,Janus激酶(JAK)2的选择性抑制剂一直受到需求;然而,V617F致癌性的结构基础直到最近才被阐明。新的结构研究揭示了激酶结构域之外的其他JAK2结构域在致病信号传导中的作用。在这里,我们评估了导致最近批准的I型JAK2抑制剂(fedratinib和pacritinib)、II型(BBT594和CHZ868)和正在开发的假激酶抑制剂(JNJ7706621)的基于结构的方法。随着全长JAK同源二聚体结构的出现,可以预见到优越的选择性和突变特异性JAK2抑制剂。意义:目前用于治疗MPNs的JAK抑制剂对症状管理有效,但对疾病根除无效,主要是因为它们对突变克隆没有强选择性。基于计算和结构的药物发现方法的兴起,以及全长JAK二聚体复合物的知识,为开发针对病理性JAK2信号驱动的一系列疾病的更好靶向治疗提供了独特的机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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