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.

摘要/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，血液 近几十年来，感染率增加了 200% 以上，这与感染者人数的增加有关 由于癌症、器官移植和艾滋病毒治疗而导致免疫功能受损。临床较差 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 以及对它们针对的三种主要作用模式中每一种的临床耐药性的出现。 蛋白激酶已成为多种疾病药物开发中回报丰厚的靶标， 从癌症到代谢紊乱，但激酶作为一类在医学领域尚未完全开发出来。 寻求新的抗真菌药物。为了开始填补这一空白，我们测试了一组特征良好、结构多样的面板 针对白色念珠菌（最常见的人类真菌）耐药分离株的活性激酶抑制剂 病原。该筛选鉴定了几种对白色念珠菌具有活性的化合物以及新兴的 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 Yck2 是广泛表达的酪蛋白激酶 1 (CK1) 家族的真菌成员。使用 通过遗传技术，我们证实 Yck2 是在宿主相关条件下培养物生长所必需的， 维持培养物中的棘白菌素抗性所需，并使抗棘白菌素梭菌具有毒力。 免疫功能正常和免疫受损的小鼠中的白色念珠菌。现在，我们将利用选择性句柄 Yck2 激酶结构域与我们的先导抑制剂和其他几种抑制剂复合物的共晶结构揭示了这一点 优化效力、真菌选择性和药理学特性。追求两个并行的脚手架 去风险策略，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先导化合物 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： 目标 1：具有改进抗真菌活性的 Yck2 抑制剂的结构合成 目标 2：优化真菌 Yck2 抑制剂的细胞和整体动物药理学 目标 3：通过耐药临床评估全身真菌感染小鼠模型的耐受性和疗效 同时进行或不进行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 Yck2 抑制剂预计在体内具有单药活性： 以及逆转/预防对棘白菌素的耐药性。这些化合物的开发将具有无价的价值 不仅从建立新的发现和开发目标空间的角度来看 机制上不同的单药抗真菌药，而且还开创了抗耐药性组合 抗真菌治疗方法已被证明对于控制其他传染病至关重要。