Lead Optimization of DHODH Inhibitors for Malaria

疟疾 DHODH 抑制剂的先导优化

• 批准号: 10736209
• 负责人: Margaret A. Phillips
• 金额: $ 75.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736209
• 关键词: Active Sites; Africa; African; Age; Amino Acids; Anabolism; Antimalarials; Artemisinins; Binding; Binding Sites; Biological Assay; Calorimetry; Cessation of life; Chemicals; Chemistry; Chemoprevention; Child; Clinical; Collaborations; Communicable Diseases; Complex; Computer Models; Development; Dihydroorotate Dehydrogenase Inhibitor; Dihydroorotate dehydrogenase; Disease; Dose; Drug Design; Drug Kinetics; Drug resistance; Effectiveness; Enzyme Inhibitor Drugs; Enzymes; Flavin Mononucleotide; Free Energy; Funding; Gene Amplification; Generations; Goals; Half-Life; Hot Spot; Human; Hydrogen Bonding; In Vitro; Kinetics; Learning; Ligands; Malaria; Measures; Medicine; Metabolic; Mitochondria; Modeling; Molecular Conformation; Mutation; Outcome; Parasite resistance; Parasites; Parasitology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasmodium; Point Mutation; Population; Property; Pyrazoles; Pyrimidine; Pyrroles; Resistance; Resistance development; Risk; Roentgen Rays; Series; Solubility; Source; Structure; Study models; Surface Plasmon Resonance; Testing; Thermodynamics; Time; Toxic effect; Validation; Work; candidate selection; chemical property; clinical development; combat; design; disorder control; drug candidate; drug discovery; efficacy study; improved; in silico; in vivo; inhibitor; lead optimization; lipophilicity; molecular dynamics; mutant; nanomolar; next generation; novel; novel therapeutics; orotate; phase 2 study; pre-clinical; preclinical development; pressure; programs; resistance allele; resistance frequency; resistance mechanism; safety study; scaffold; targeted treatment

Project Summary. Malaria puts at risk 50% of the world’s population and is responsible for nearly 600,000 yearly deaths, mostly in children under the age of five in Africa. While a large portfolio of anti-malarial agents has been used to combat the disease, drug resistance has compromised the effectiveness of most clinically approved drugs, and the recent identification of resistance alleles against the current front line artemisinin combinations in Africa threatens current disease control programs. Thus, the identification of new drugs to combat drug resistant malaria is essential to continued progress against the disease. Our group in collaboration with Medicines for Malaria Venture (MMV) validated dihydroorotate dehydrogenase as a clinically valuable drug target for the treatment of malaria through studies on triazolopyrimidine DSM265, which advanced to phase II clinical development before the project was stopped due to discovery of off-target toxicity in preclinical species. In this current proposal we are working to identify new generation DHODH inhibitors by focusing on a different chemical series from DSM265, thus not expected to share an overlapping toxicity profile. Secondly, we plan structure-based approaches to identify inhibitors that will have reduced resistance risk compared to DSM265, which selected for resistance in 2 patients treated in the Phase II study. In aim one we plan to complete lead optimization of three related pyrazole-based DHODH inhibitor series, identified by scaffold hop using computational approaches (in collaboration with Schrödinger) from a pyrrole series we completed work on during the current fund period. Compounds from our pyrazole series have demonstrated high potency (sub nanomolar to low micromolar), and a reduced propensity to select for resistant parasites in vitro. We have a strong understanding of the SAR around these series, including the potency drivers, and the metabolic hot spots, and we plan mix and match chemistry to identify compounds with improved metabolic stability that will support human half-life (>100 h) and dosing targets (< 500 mg) set out by MMV. In aims 2 and 3 we use a combination of experimental and computational approaches (Schrödinger) to define the enzyme:ligand kinetic and thermodynamic binding properties that are associated with reduced resistance risk, as well as to correlate resistance risk to compound physical chemical properties. Computational models and measured thermodynamic/kinetic parameters will inform design and synthesis of new compounds predicted to have reduced resistance risk. The DHODH program is ideally suited to study the contribution of binding energetics to resistance propensity, as we have a wealth of structural information over three different chemical series with different physical chemical properties and alternative binding modes to the enzyme active site. Successful completion of these aims will allow identification of the strongest DHODH candidate for further clinical development, and it will provide key learnings on how to navigate resistance issues in target-based drug discovery programs for proliferative diseases in general, increasing the impact of our studies.

项目摘要。疟疾使世界50%的人口处于危险之中， 每年的死亡人数，主要是非洲五岁以下的儿童。虽然大量的抗疟疾药物组合 已经被用来对抗这种疾病，耐药性已经损害了大多数临床药物的有效性。 批准的药物，以及最近发现的针对当前一线青蒿素的耐药等位基因 非洲的联合用药威胁着当前的疾病控制计划。因此，新药的鉴定， 防治抗药性疟疾对于继续在防治这一疾病方面取得进展至关重要。本集团在 与疟疾新药开发公司（MMV）合作，验证了二氢乳清酸脱氢酶作为临床 通过对三唑并嘧啶DSM 265的研究， 在项目因发现脱靶毒性而停止之前，已进入II期临床开发阶段 在临床前物种中。在目前的提案中，我们正在努力通过以下方式鉴定新一代DHODH抑制剂： 侧重于与DSM 265不同的化学系列，因此预计不会共享重叠的毒性特征。 其次，我们计划基于结构的方法来鉴定具有降低的耐药风险的抑制剂 与DSM 265相比，DSM 265在II期研究中治疗的2名患者中选择了耐药。在目标一，我们 计划完成三个相关吡唑类DHODH抑制剂系列的先导优化， 支架跳跃使用计算方法（与薛定谔合作）从吡咯系列，我们 在本基金期间完成的工作。我们的吡唑系列化合物已经证明 高效力（亚纳摩尔至低微摩尔），以及降低的选择抗性寄生虫的倾向， 体外我们对这些系列的SAR有很强的理解，包括效力驱动程序，以及 代谢热点，我们计划混合和匹配化学，以确定化合物与改善代谢 这将支持MMV设定的人体半衰期（>100小时）和剂量目标（< 500 mg）。在aims 2中 和3，我们使用实验和计算方法（薛定谔）的组合来定义 酶：配体动力学和热力学结合特性与降低的耐药风险相关， 以及将抗性风险与化合物的物理化学性质相关联。计算模型和 测量的热力学/动力学参数将为设计和合成新化合物提供信息， 降低了耐药风险。DHODH程序非常适合研究结合的贡献 能量学的阻力倾向，因为我们有丰富的结构信息，在三个不同的化学 具有不同的物理化学性质和与酶活性位点的替代结合模式的系列。 成功完成这些目标将允许确定最强的DHODH候选人， 临床开发，它将提供关于如何在基于目标的药物治疗中解决耐药性问题的关键知识。 药物发现计划一般增殖性疾病，增加我们的研究的影响。

项目成果

Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening.

• DOI: 10.1021/acs.jcim.5b00680
• 发表时间: 2016-03-28
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Pavadai E;El Mazouni F;Wittlin S;de Kock C;Phillips MA;Chibale K
• 通讯作者: Chibale K

Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii.

• DOI: 10.1073/pnas.2213116119
• 发表时间: 2022-12-20
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).

• DOI: 10.1021/acs.jmedchem.5b00606
• 发表时间: 2015-07-23
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lucas-Hourani M;Munier-Lehmann H;El Mazouni F;Malmquist NA;Harpon J;Coutant EP;Guillou S;Helynck O;Noel A;Scherf A;Phillips MA;Tangy F;Vidalain PO;Janin YL
• 通讯作者: Janin YL

Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.

• DOI: 10.1021/acs.jmedchem.0c02022
• 发表时间: 2021-03-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lawong A;Gahalawat S;Okombo J;Striepen J;Yeo T;Mok S;Deni I;Bridgford JL;Niederstrasser H;Zhou A;Posner B;Wittlin S;Gamo FJ;Crespo B;Churchyard A;Baum J;Mittal N;Winzeler E;Laleu B;Palmer MJ;Charman SA;Fidock DA;Ready JM;Phillips MA
• 通讯作者: Phillips MA

Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.

• DOI: 10.1021/acs.jmedchem.6b00275
• 发表时间: 2016-06-09
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Kokkonda S;Deng X;White KL;Coteron JM;Marco M;de Las Heras L;White J;El Mazouni F;Tomchick DR;Manjalanagara K;Rudra KR;Chen G;Morizzi J;Ryan E;Kaminsky W;Leroy D;Martínez-Martínez MS;Jimenez-Diaz MB;Bazaga SF;Angulo-Barturen I;Waterson D;Burrows JN;Matthews D;Charman SA;Phillips MA;Rathod PK
• 通讯作者: Rathod PK