Optimization of Lead BKIs for Cryptosporidiosis Therapy

用于隐孢子虫病治疗的先导 BKI 的优化

• 批准号: 10540344
• 负责人: WESLEY C VAN VOORHIS
• 金额: $ 80.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540344
• 关键词: 3-Dimensional; Address; Animals; Back; Blood Chemical Analysis; Canis familiaris; Cardiac; Cardiovascular system; Cause of Death; Characteristics; Child; Chondrocytes; Clinical; Country; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Development; Diarrhea; Disease; Dose; Drug Kinetics; Dysplasia; Embryonic Development; Fetal Development; Fetal safety; Grant; Growth; Hemorrhage; Histopathology; Human; Immunocompromised Host; Impairment; In Vitro; Individual; Infection; Interferon Type II; Knockout Mice; Lead; MAP2K1 gene; Malnutrition; Mammalian Cell; Metabolic Pathway; Modeling; Morbidity - disease rate; Mus; Neurologic; Newborn Infant; Oral; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Plasma; Polymorph; Predisposition; Pregnancy; Property; Rattus; Research; Resources; Safety; Sampling; Solubility; Structure-Activity Relationship; Symptoms; Target Populations; Testing; Therapeutic; Therapy trial; Toxic effect; Toxicity Tests; Toxicology; Vaccines; Zebrafish; bone; calcium-dependent protein kinase; cytotoxicity; design; dosage; drug candidate; efficacy testing; improved; in vivo; inhibitor therapy; kinase inhibitor; lead optimization; manufacture; manufacturing scale-up; mortality; motility disorder; nitazoxanide; novel; novel therapeutics; pathogen; porcine model; pre-clinical; programs; response; safety study; safety testing; screening

ABSTRACT: Optimization of Lead BKIs for Cryptosporidiosis Therapy The broad, long-term objective of this research is to develop a therapeutic for treatment of Cryptosporidium infection. Cryptosporidium infection causes persistent diarrhea (cryptosporidiosis) that is associated with increased morbidity and mortality in children and immunocompromised individuals. Cryptosporidium is one of the most important pathogens leading to poor outcomes in <2-yo malnourished children in resource poor countries, including >3-fold mortality and strong associations with stunting and impaired neurological development. The only available therapeutic, nitazoxanide, does not work in immunocompromised individuals and has <30% efficacy in malnourished children. New therapeutics for Cryptosporidium are badly needed. We have been developing bumped-kinase inhibitors (BKIs) that selectively target Cryptosporidium calcium- dependent protein kinase 1 (CDPK1) as therapeutics for cryptosporidiosis. In our program, our leads have performed very well, demonstrating efficacy at low oral dosages in mouse, calf, and piglet models of C. parvum and C. hominis, while retaining almost all the favorable safety aspects consistent with a late lead. However, safety issues with BKI leads have stopped us from developing current late leads. We now understand the safety issues associated with late BKI leads and have found these safety issues are not inextricably associated with the structure-activity relationship (SAR) of BKIs’ efficacy against cryptosporidiosis. In this proposal, we will use the efficacy and safety SAR to help drive medicinal chemistry towards a late pre-clinical lead with safety, pharmacokinetic, and efficacy properties that can be developed for treatment in the target population of <2-yo malnourished children and immunocompromised individuals. The Aims are: AIM 1) Establish late leads for cryptosporidiosis therapy, including Subaims 1A) In vitro efficacy and safety testing, 1B) IFN- γ -KO mouse nLuc-C. parvum efficacy testing, 1C) Mouse multidosing, 7d safety testing, 1D) Determine metabolites of BKIs, and, 1E) Design and synthesize new BKIs; AIM 2) Test novel late leads in calf clinical model for cryptosporidiosis; and, AIM 3) Assess advanced late leads for late safety testing, including subaims 3A) Bone safety testing, 3B) Pregnancy/developmental/fetal safety testing; 3C) Rat and dog cardiovascular (CV) safety testing, and, 3D) Pre-GLP safety and polymorph testing. At the end of the grant period, we expect to have a preclinical lead and at least one back up molecule that is ready to move into GLP safety testing, pre-GMP manufacturing scale up, and IND filing to move towards human trials for a BKI for therapy of cryptosporidiosis.

文章摘要：隐孢子虫病治疗用铅BKI的优化 这项研究的广泛和长期目标是开发一种治疗隐孢子虫的方法。 感染。隐孢子虫感染引起持续性腹泻(隐孢子虫病)，与 儿童和免疫功能受损个人的发病率和死亡率增加。隐孢子虫是 资源贫乏地区2-YO营养不良儿童预后不良的最主要病原体 国家，包括三倍的死亡率和与发育迟缓和神经受损的强烈关联 发展。唯一可用的治疗方法是硝唑尼特，对免疫功能低下的人无效。 对营养不良的儿童有30%的疗效。迫切需要治疗隐孢子虫的新疗法。我们 一直在开发能选择性靶向隐孢子虫钙的BKIs。 CDPK1作为治疗隐孢子虫病的药物。在我们的节目中，我们的主演有 效果非常好，在小鼠、牛犊和仔猪模型上显示了低剂量口服的效果。 和人源虫，同时保留了与后期领先一致的几乎所有有利的安全方面。然而， BKI引线的安全问题阻止了我们开发当前的晚期引线。我们现在理解了 与BKI后期线索相关的安全问题，并发现这些安全问题并不是千丝万缕的 与BKI抗隐孢子虫病疗效的构效关系(SAR)相关。在这项提案中，我们将 使用有效性和安全性SAR帮助推动药物化学以安全的方式迈向晚期临床前领先， 可在目标人群中开发用于治疗的药代动力学和疗效特性 营养不良的儿童和免疫功能受损的个人。目标是：目标1)为以下目标建立后期销售线索 隐孢子虫病治疗，包括1B)干扰素-γ-KO小鼠 NLuc-C小鼠药效试验，1C)小鼠多次给药，7d安全性试验，1d)测定BKI的代谢物， 以及，1E)设计和合成新的BKI；目的2)测试新的小牛临床模型的晚期导联 隐孢子虫病；以及，目标3)评估晚期安全性测试的晚期导联，包括亚目标3A)骨 安全测试，3B)怀孕/发育/胎儿安全测试；3C)大鼠和狗心血管(CV)安全 测试，以及，3D)GLP前安全性和多态测试。在授权期结束时，我们预计将有一个 临床前铅和至少一个准备进入GLP安全测试的后备分子 扩大生产规模，并提交IND申请，以进行BKI治疗隐孢子虫病的人体试验。