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。疟疾占世界人口的50％，并负责近60万 每年死亡，主要是在非洲五岁以下的儿童。虽然大量的反车祸投资组合 已被用来打击这种疾病，耐药性损害了大多数临床上的有效性 批准的药物，以及最近对当前前线artemisinin的电阻等位基因的识别 非洲的组合威胁当前的疾病控制计划。那，将新药识别为 抗战斗力抗药性疟疾对于继续反对这种疾病至关重要。我们的小组 与疟疾风险药物（MMV）合作验证了二氢甲前酸脱氢酶作为临床上 有价值的药物靶标可通过研究三唑吡啶DSM265的研究来治疗疟疾 由于发现了脱靶毒性，因此在该项目停止之前先升至II期临床开发 在临床前物种。在当前的建议中，我们正在努力确定新一代Dhodh抑制剂 专注于与DSM265的不同化学系列，因此预计不会具有重叠的毒性概况。 其次，我们计划基于结构的方法来识别将降低阻力风险的抑制剂 与DSM265相比，在第二阶段研究中接受了2例治疗的患者中选择抗性。在一个目标中我们 计划完成三个基于吡唑的Dhodh抑制剂系列的铅优化，并确定 使用计算方法（与schrödinger合作）的脚手架跳跃节目系列 在当前基金期间完成了工作。我们吡唑系列的化合物已经证明了 高效力（亚纳摩尔至低微摩尔），并降低了选择抗性寄生虫的倾向 体外。我们对围绕这些系列的SAR有深刻的了解，包括效力驱动程序和 代谢热点，我们计划混合和匹配化学反应，以鉴定具有改进代谢的化合物 稳定性将支持人类半衰期（> 100 h）和MMV列出的给药靶标（<500 mg）。在目标2中 3我们使用实验和计算方法（Schrödinger）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， 以及将耐药风险与复合物理化学特性相关联。计算模型和 测得的热力学/动力学参数将为预测的新化合物的设计和合成提供信息 降低了阻力风险。 DHODH计划非常适合研究结合的贡献 抵抗可靠性的能量学，因为我们在三种不同的化学上拥有大量的结构信息 具有不同物理化学特性和替代结合模式的序列与酶活性位点。 这些目标的成功完成将允许确定强大的Dhodh候选人 临床开发，它将提供有关如何在基于目标中应对阻力问题的关键知识 一般来说，用于增殖疾病的药物发现计划，增加了我们研究的影响。

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

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

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

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

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