Mechanisms of drug resistance in Myeloproliferative neoplasms treated with JAK2 i

描述(申请人提供)：在造血干细胞中表达具有结构性活性的JAK2激酶足以在小鼠中诱导骨髓增生性肿瘤(MPN)，为开发JAK2靶向治疗铺平了道路。最近JAK2抑制剂(INCB018424和TG101348)在治疗MPN患者方面的临床成功是有希望的，这两种临床药物很有可能被FDA批准用于治疗JAK2介导的疾病。考虑到激酶的结构可塑性和对激酶抑制剂治疗的耐药性，我们预计对JAK2抑制剂的耐药性也会发展。此外，我们目前对JAK2调控机制的理解是推测的。例如，体细胞突变如何激活激酶还不完全清楚，这限制了我们开发有效的治疗开发。突变研究与电子结构建模相结合，提供了更好的结构-功能洞察、患者管理和药物设计。为此，我们建议鉴定JAK2临床抑制剂的耐药突变，以了解JAK2耐药的机制和JAK2的调控机制。我们的初步数据表明，与TG101348相比，对INCB018424的抗性频率更高，这表明它们对不同的激酶构象具有选择性。我们推测，这些抑制物将针对不同的突变星座进行选择，并可能相互补充以抑制耐药性的发展。在这项研究中，我们建议结合生化和结构特征进行突变研究，以了解耐药的机制和JAK2的调节，这将有助于我们的患者诊断、药物设计和制定对抗临床耐药的策略。

DESCRIPTION (provided by applicant): The expression of constitutively active JAK2 kinase in hematopoietic stem cells is sufficient to induce myeloproliferative neoplasms (MPNs) in mice paved the way for developing JAK2-targeted therapies. Recent clinical success of JAK2 inhibitors (INCB018424 and TG101348) in the treatment of MPN patients are promising, and most likely these two clinical agents will be approved by FDA for the treatment of JAK2 mediated disorders. Given the structural plasticity in kinases and emergence of resistance to kinase inhibitor therapy we anticipate that resistance to JAK2 inhibitors will develop as well. Additionally, our current understandings of JAK2 regulatory mechanisms are speculative. For instance, how somatic mutations activate the kinase is not fully understood that limits us to develop efficient therapeutic development. Mutagenesis studies coupled with in silico structural modeling provide greater structural-functional insights, patient management and drug design. Toward this end, we propose to identify the drug resistant mutations for JAK2 clinical inhibitors to understand the mechanisms of drug resistance and JAK2 regulatory mechanisms. Our preliminary data suggests that the frequency of resistance against INCB018424 is higher as compared to TG101348 suggesting their selectivity for distinct kinase conformations. We hypothesize that these inhibitors will select for different constellation of mutations and may complement each other to suppress the development of resistance. In this study, we propose to perform mutational studies coupled with biochemical and structural characterization to understand the mechanisms of drug resistance and JAK2 regulation that will help us patient diagnosis, drug design and developing strategies to combat clinical resistance.