Small Molecule Inhibitors of ZAP-70 for the Treatment of Autoimmune Disorders

ZAP-70 小分子抑制剂用于治疗自身免疫性疾病

• 批准号: 8520902
• 负责人: Mark Gallop
• 金额: $ 30万
• 依托单位: NURIX, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520902
• 关键词: Affect; Affinity; Antigens; Arts; Autoimmune Diseases; Back; Binding; Biochemical; Biological Assay; Biological Products; CD3 Antigens; Calcium; Catalytic Domain; Cell Line; Cell physiology; Cells; Cellular biology; Clinical; Communities; Confidential Information; Conserved Sequence; Cytoplasmic Protein; Cytoplasmic Tail; Cytotoxic T-Lymphocytes; Data Set; Development; Disease; Enzymes; Financial Support; Forcible intercourse; Fostering; Funding; Gene Silencing; Grant; Homologous Transplantation; Human; Immunologic Deficiency Syndromes; Immunosuppressive Agents; In Vitro; Investments; Lead; Length; Licensing; Lupus; Malignant Neoplasms; Mediating; Mitogens; Modeling; Molecular Conformation; Multiple Sclerosis; Mus; Mutagenesis; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Organ; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Play; Production; Protein Tyrosine Kinase; Psoriasis; Receptor Signaling; Regulation; Research; Research Activity; Rheumatoid Arthritis; Role; Secure; Series; Signal Transduction; T cell regulation; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Therapeutic; Therapeutic immunosuppression; Transgenic Mice; Transplantation; Tyrosine; Work; ZAP-70 Gene; base; chemical genetics; common treatment; cytokine; drug discovery; inhibitor/antagonist; innovation; insight; interest; kinase inhibitor; mouse model; mutant; peripheral blood; pre-clinical; programs; protein protein interaction; public health relevance; small molecule; src Homology Region 2 Domain; src-Family Kinases; success; therapeutic development; therapeutic target; tool; zeta chain antigen T cell receptor

DESCRIPTION (provided by applicant): ZAP-70 is a cytoplasmic protein tyrosine kinase that plays a critical function in T cell antigen receptor (TCR) signaling and in most aspects of T cell biology. ZAP-70 is an attractive therapeutic target for treatment of prevalent human T-cell dependent autoimmune diseases (e.g. rheumatoid arthritis, lupus, multiple sclerosis, psoriasis) and in allogenic transplantation. Considerable effort has previously been expended to develop specific ZAP-70 catalytic site inhibitors, without success, likely due to specific structural attributes of the kinase catalytic domain. Following TCR stimulation, the ZAP-70 tandem SH2 domains associate with dual tyrosine phosphorylated residues located within conserved sequence motifs (referred to as ITAMs) of the cytoplasmic domains of the CD3 and zeta chains of the TCR. Mutagenesis and structural studies on full-length ZAP-70 have shown that, prior to association with the ITAMs, ZAP-70 exists in an autoinhibited conformation in which the tandem SH2 domains stabilize an inactive conformation of the kinase domain. This proposal is built on the effort of the Kuriyan and Weiss labs in an NIAMS-funded 2009 ARRA Grand Opportunity grant to identify small molecules that stabilize the autoinhibited conformation of ZAP-70 and serve as allosteric inhibitors of the kinase. That successful research program led to development of a series of specific biochemical tools for identifying prototypical allosteric inhibitors of ZAP-70, and is poised to enable a dedicated new drug discovery effort in T cell regulation. In this current proposal, Nurix Inc., an emerging biopharmaceutical company founded by John Kuriyan, Art Weiss and Michael Rape, aims to extend this earlier work by optimizing the potency of allosteric inhibitors of ZAP-70 that could serve as a leads for clinical development of a new T-cell specific immunosuppressant. The program will (i) seek insight into the mode of interaction of these small molecule inhibitors with ZAP-70 using crystallographic and other biophysical techniques to facilitate lead optimization, and (ii) examine the activity of allosteric inhibitor compounds in established models of T cell function.

描述（由申请人提供）：ZAP-70是一种细胞质蛋白酪氨酸激酶，在T细胞抗原受体（TCR）信号传导和T细胞生物学的大多数方面发挥关键作用。ZAP-70是用于治疗流行的人类T细胞依赖性自身免疫疾病（例如类风湿性关节炎、狼疮、多发性硬化、牛皮癣）和同种异体移植的有吸引力的治疗靶标。以前已经花费了相当大的努力来开发特异性ZAP-70催化位点抑制剂，但没有成功，这可能是由于激酶催化结构域的特定结构属性。在TCR刺激后，ZAP-70串联SH 2结构域与位于TCR的CD 3和ζ链的胞质结构域的保守序列基序（称为ITAM）内的双酪氨酸磷酸化残基缔合。对全长ZAP-70的诱变和结构研究表明，在与ITAM结合之前，ZAP-70以自抑制构象存在，其中串联的SH 2结构域稳定激酶结构域的非活性构象。 这项提议是建立在Kuriyan和韦斯实验室在NIAMS资助的2009年ARRA Grand Opportunity赠款中的努力之上的，该项目旨在鉴定稳定ZAP-70自抑制构象并作为激酶变构抑制剂的小分子。该成功的研究计划导致开发了一系列特定的生化工具，用于识别ZAP-70的原型变构抑制剂，并准备在T细胞调节方面进行专门的新药发现工作。在目前的提案中，Nurix Inc.，由JohnKuriyan、Art韦斯和MichaelRape创立的新兴生物制药公司旨在通过优化ZAP-70的变构抑制剂的效力来扩展这一早期工作，该变构抑制剂可以作为新的T细胞特异性免疫抑制剂的临床开发的先导。该计划将（i）寻求洞察这些小分子抑制剂与ZAP-70的相互作用模式，使用晶体学和其他生物物理技术促进铅优化，以及（ii）检查变构抑制剂化合物在已建立的T细胞功能模型中的活性。