DBM Anti-Proliferative Lead Small Molecules for Polycystic Kidney Disease

DBM 抗增殖铅小分子治疗多囊肾病

• 批准号: 8892174
• 负责人: Erik Mills Schwiebert
• 金额: $ 63.17万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892174
• 关键词: Achievement; Affect; Apoptosis; Attenuated; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Award; Basic Science; Benchmarking; Biochemical; Biological Assay; Biological Products; Cancer cell line; Cell Culture Techniques; Cell Cycle Arrest; Cell Line; Cells; Cellular biology; Chemicals; Chronic; Clinical; Clinical Trials; Collaborations; Critical Pathways; Cyst; Cystic kidney; Cytostatics; Data; Development; Developmental Therapeutics Program; Disease; Dose; Epithelial; Epithelial Cells; Event; Exhibits; FDA approved; Family; Funding; Future; Genetic; Germ Cells; Goals; Growth; Health; Hereditary Disease; Human; Image; In Vitro; Kidney; Lead; Licensing; M Phase Arrest; Malignant Neoplasms; Malignant neoplasm of prostate; Marketing; Methods; Modification; Molecular; Molecular Mechanisms of Action; Monitor; Mus; National Cancer Institute; Normal Cell; Oral Administration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Polycystic Kidney Diseases; Primary Cell Cultures; Prostate; Publications; Renal carcinoma; Research; Science; Series; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Staging; Structure-Activity Relationship; System; Testing; Therapeutic; Tissues; Validation; Work; absorption; analog; arm; base; cancer cell; cell growth; cytotoxic; cytotoxicity; design; drug candidate; drug development; drug discovery; in vivo; interest; mouse model; novel; novel therapeutics; pre-clinical; programs; research study; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): An important discovery and validation event occurred recently within human cell-based drug discovery programs at DiscoveryBioMed, Inc. (DBM), yielding a lead class of cytostatic anti-proliferative small molecules that display nanomolar potency and marked efficacy against hyperproliferative human PKD cells that create and line remodeled PKD cysts within emergent cystic kidney tissue. DBM's strength for this program is our ability to culture and implement primary human cells from normal and diseased kidneys and the deep expertise and record of publication in the PKD field by DBM's Founder. DBM implemented these primary human PKD cell systems in the Critical Path for drug discovery and validation and will continue to implement said human diseased cell platforms in continued proposed work. There are no PKD-specific therapeutics emerging as yet or that are approved by the FDA. Existing PKD drugs in development and trials are 're-purposed' from other disease programs. Therefore, there is significant and critical unmet clinical need for small molecule therapies for PKD. DBM also sees this drug class as a PKD preventative; a drug against ADPKD development would be particularly effective given the slow progression/enlargement of kidneys over several decades that is monitored by imaging within families historically afflicted by this autosomal dominant disease. Medicinal chemistry-driven modification is this lead drug class is on-going and has yielded nanomolar potency against PKD and across a wide spectrum of cancers and is specific in effect to cystic or cancer cells versus normal cells. This DBM 43H11 program is accelerated for typical Phase 1 SBIR status. Because of this, because of a critical subcontracted collaboration with the Johns Hopkins PKD Center and because of the critical unmet clinical need for new PKD-specific therapeutics, DBM applies for a Phase 1/Phase 'Fast Track' award to accelerate this program from its current pace into clinical trials. Over-arching goals and milestones for Phase 1 of the program include, to: (a) advance and finalize basic medicinal chemistry derivatization of lead small molecules; (b) perform comprehensive cellular and molecular mechanism of action (MoA) assessment; and (c) generate proof of concept in vivo efficacy in a novel PKD mouse model. Lead drugs will be administered and assessed in PKD mice in collaboration with the Johns Hopkins PKD Center. Armed with these Phase 1 achievements already in progress on this DBM 43H11 lead drug class, planned Phase 2 milestones are scripted to: (d) refine medicinal chemistry for in vivo 'druggability'; (e) define cellular and molecular MoA(s) fully and specifically; (f) perform ADME/DMPK for a full pre-clinical profile; and (g) select lead clinical candidates for an IND filing and PKD clinical trials planning. The best clinical candidate drug will be developed forward by DBM in conjunction with Johns Hopkins PKD Center, a medicinal chemistry CRO, and an ADME/DMPK CRO in envisioned Phase 2 efforts for a future out-license partnership with a BioPharmaceutical company. BM, Ic.

描述（由申请人提供）：一个重要的发现和验证事件最近发生在DiscoveryBiemed，Inc。（DBM）的基于人类细胞的药物发现计划中，产生了铅类替代抗增殖性小分子的铅类，这些分子表现出纳米尔效力和明显的功效针对在新兴囊性肾脏组织中产生和线重塑的PKD囊肿的高增殖性人PKD细胞。 DBM对该计划的实力是我们从正常和患病的肾脏中培养和实施原代人细胞的能力，以及DBM创始人在PKD领域的深厚专业知识和发表记录。 DBM在药物发现和验证的关键途径中实施了这些主要的人类PKD细胞系统，并将继续在持续建议的工作中实施人类患病细胞平台。尚无FDA尚无PKD特异性治疗药。现有的开发中的PKD药物和试验是从其他疾病计划中“重新塑造的”。因此，对PKD的小分子疗法存在明显且至关重要的未满足的临床需求。 DBM还认为该药物类是PKD预防剂。鉴于几十年来肾脏的进展缓慢/肾脏的进展缓慢/肿大，这种反对ADPKD开发的药物将特别有效。 这种常染色体显性疾病。药物化学驱动的修饰是该铅药物类别正在进行中，并且对PKD和广泛的癌症产生了纳摩尔效力，并且对囊性或癌细胞而言与正常细胞相对于癌细胞有效。该DBM 43H11程序的典型第1阶段SBIR状态加速。因此，由于与Johns Hopkins PKD中心进行了严格的分包合作，并且由于对新PKD特定治疗的临床需求的至关重要，DBM适用于第1阶段/阶段的“快速轨道”奖，以从其中加速该计划。当前进入临床试验的速度。该计划的第1阶段的超大目标和里程碑包括：（a）提前和最终确定铅小分子的基本药物化学衍生化； （b）进行全面的细胞和分子作用机理（MOA）评估； （c）在新型的PKD小鼠模型中生成体内功效的概念证明。铅药物将与约翰·霍普金斯PKD中心合作在PKD小鼠中进行管理和评估。在此DBM 43H11铅毒品类别中已经进行了这些阶段1的成就，计划的2阶段里程碑脚本为：（d）精炼体内“可药物”的药物化学； （e）完全，具体地定义细胞和分子MOA； （f）执行完整的临床前轮廓的ADME/DMPK； （g）选择IND归档和PKD临床试验的铅临床候选者 规划。最好的临床候选药物将由DBM与Johns Hopkins PKD中心，药物化学CRO和ADME/DMPK CRO一起开发，并在Invisioned 2阶段的第2阶段努力中与生物制药公司建立未来的超许可合作伙伴关系。 BM，IC。