Targeting the casein kinase 1 (CK1)-like kinase Yck2 in fungal pathogenesis

在真菌发病机制中靶向酪蛋白激酶 1 (CK1) 样激酶 Yck2

• 批准号: 10437100
• 负责人: LEAH Elizabeth Cowen
• 金额: $ 62.59万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-22 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437100
• 关键词: Achievement; Animals; Antifungal Agents; Antifungal Therapy; Biochemical; Biological Assay; Biology; Candida albicans; Candida auris; Cell Culture Techniques; Cells; Chemicals; Chemistry; Clinical; Collaborations; Communicable Diseases; Complex; Crystallization; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Economics; Family; Foundations; Future; Genetic; Genetic Techniques; Genomic approach; Goals; Growth; HIV; Health; Human; Immune; Immunocompetent; Industry; Infection; Lead; Life; Longevity; Malaria; Malignant Neoplasms; Measures; Medicine; Metabolic; Metabolic Diseases; Methods; Molecular Biology; Mus; Mycoses; Organ Transplantation; Organism; Outcome; Pathogenesis; Persons; Pharmacology; Phosphotransferases; Predisposition; Property; Protein Kinase; Regimen; Research; Resistance; Rewards; Risk; Schedule; Sepsis; Structure; Systemic infection; Testing; Therapeutic; Toxic effect; Tuberculosis; Virulence; Work; analog; base; blood-brain barrier permeabilization; cancer therapy; casein kinase I; design; drug candidate; drug development; drug resistant pathogen; echinocandin resistance; emerging pathogen; experience; immune function; improved; in vitro Assay; in vivo; inhibitor; kinase inhibitor; liver metabolism; member; mouse model; multidisciplinary; pathogen; pathogenic fungus; prevent; scaffold; structural biology; treatment strategy

Summary/Abstract Fungal pathogens have an enormous impact on human health worldwide. In the U.S. alone, bloodstream infections have increased by over 200% in recent decades, associated with an increasing number of people with compromised immune function due to treatment for cancer, organ transplantation, and HIV. Poor clinical outcome for most invasive fungal infections is attributable to the very limited number of effective antifungals available and the emergence of clinical resistance to each of the three main modes of action they target. Protein kinases have emerged as richly rewarding targets in the development of drugs for diverse diseases, ranging from cancer to metabolic disorders, but kinases as a class have remained completely untapped in the quest for new antifungals. To begin to fill this void, we tested a panel of well-characterized, structurally diverse kinase inhibitors for activity against a drug-resistant isolate of Candida albicans, the most common human fungal pathogen. This screen identified several compounds which were active against C. albicans and the emerging pathogen, Candida auris. Using chemical genomic approaches, we established the primary target of our most active compounds as Yck2, a fungal member of the widely expressed casein kinase 1 (CK1) family. Using genetic techniques, we confirmed that Yck2 is required for growth in culture under host-relevant conditions, is required to maintain echinocandin-resistance in culture, and enables the virulence of echinocandin-resistant C. albicans in both immune-competent and immune-compromised mice. Now, we will exploit selectivity handles revealed by co-crystal structures of the Yck2 kinase domain in complex with our lead and several other inhibitors to optimize potency, fungal selectivity, and pharmacological properties. Pursuing two scaffolds in parallel as a de-risking strategy, our goal is to deliver one or more advanced leads for future development of a clinical drug candidate. To achieve this goal, our multidisciplinary team will use its expertise in chemistry, structural biology, pharmacology, and fungal biology to pursue the following aims: AIM 1: Structure-enabled synthesis of Yck2 inhibitors with improved antifungal activity AIM 2: Optimize cellular and whole animal pharmacology of fungal Yck2 inhibitors AIM 3: Evaluate tolerability and efficacy in mouse models of systemic fungal infection by drug-resistant clinical isolates with and without concurrent sub-therapeutic echinocandin treatment The Yck2 inhibitors we develop in achieving these aims are expected to possess single agent activity in vivo as well as reverse/prevent resistance to echinocandins. The development of these compounds will be invaluable not only from the perspective of establishing a new target space for discovery and development of mechanistically distinct single-agent antifungals but also in pioneering a resistance-aversive combination approach to antifungal therapy that has proven essential in controlling other infectious diseases.

总结/摘要 真菌病原体对全世界人类健康产生巨大影响。仅在美国， 近几十年来，感染人数增加了200%以上，这与越来越多的人 由于癌症、器官移植和艾滋病毒治疗，免疫功能受损。不良临床 大多数侵袭性真菌感染的结果可归因于有效抗真菌药物的数量非常有限 目前，这些药物的市场前景不容乐观，并且出现了对它们所针对的三种主要作用模式中的每一种的临床耐药性。 蛋白激酶已经成为开发用于各种疾病的药物的富有回报的靶点， 从癌症到代谢紊乱，但是激酶作为一类在医学上仍然完全未被开发。 寻找新的抗真菌药物为了开始填补这一空白，我们测试了一组特征良好、结构多样的 激酶抑制剂，用于对抗白色念珠菌的耐药性分离株的活性，白色念珠菌是最常见的人类真菌 病原体该筛选鉴定了几种对C.白色念珠菌和新生 病原体，耳念珠菌。使用化学基因组方法，我们建立了我们最重要的主要目标， 活性化合物如Yck 2，广泛表达的酪蛋白激酶1（CK 1）家族的真菌成员。使用 通过遗传技术，我们证实了Yck 2是在宿主相关条件下培养生长所必需的， 需要在培养物中维持棘白菌素抗性，并使棘白菌素抗性C. 白念珠菌在免疫活性小鼠和免疫受损小鼠中。现在，我们将利用选择性句柄 通过Yck 2激酶结构域与我们的先导化合物和几种其他抑制剂的复合物的共晶体结构揭示 以优化效力、真菌选择性和药理学性质。平行追逐两个脚手架， 我们的目标是为临床药物的未来开发提供一个或多个先进的线索， 候选人为了实现这一目标，我们的多学科团队将利用其在化学，结构生物学， 药理学和真菌生物学，以追求以下目标： 目的1：结构使能合成具有改善的抗真菌活性的Yck 2抑制剂 目的2：优化真菌Yck 2抑制剂的细胞和整体动物药理学 目的3：通过耐药临床试验，评价系统性真菌感染小鼠模型的耐受性和有效性。 同时使用和不使用亚治疗棘白菌素治疗的分离株 我们为实现这些目标而开发的Yck 2抑制剂预期具有体内单一药剂活性， 以及逆转/防止对棘白菌素的抗性。这些化合物的发展将是无价的 不仅从建立新的发现和开发目标空间的角度， 机制上不同的单药抗真菌药物，但也开创了耐药性厌恶组合 抗真菌治疗方法已被证明是控制其他传染病的关键。