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: 8803107
• 负责人: Erik Mills Schwiebert
• 金额: $ 50.34万
• 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/8803107
• 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）：DiscoveryBioMed, Inc. (DBM) 的基于人类细胞的药物发现计划最近发生了一项重要的发现和验证事件，产生了一种领先的细胞抑制性抗增殖小分子，这些小分子对过度增殖的人类 PKD 细胞表现出纳摩尔效力和显着功效，这些细胞在新兴囊性肾组织内产生和排列重塑的 PKD 囊肿。 DBM 在该项目中的优势在于我们能够培养和实施来自正常和患病肾脏的原代人类细胞，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路径中实施了这些主要的人类 PKD 细胞系统，并将在继续提出的工作中继续实施所述人类患病细胞平台。目前还没有出现或经 FDA 批准的 PKD 特异性疗法。正在开发和试验的现有 PKD 药物是从其他疾病项目中“重新调整用途”的。因此，针对 PKD 的小分子疗法存在重大且关键的未满足临床需求。 DBM 还将此类药物视为 PKD 的预防药物；考虑到几十年来肾脏进展缓慢/增大，针对 ADPKD 发展的药物将特别有效，并且通过在历史上患有 ADPKD 的家庭中进行成像监测来监测 这种常染色体显性遗传疾病。药物化学驱动的修饰是这一主导药物类别正在进行的过程，并且已经产生了针对 PKD 和多种癌症的纳摩尔效力，并且与正常细胞相比，对囊性细胞或癌细胞具有特异性作用。此 DBM 43H11 程序针对典型的第 1 阶段 SBIR 状态进行加速。因此，由于与约翰·霍普金斯 PKD 中心的重要分包合作，并且由于对新的 PKD 特异性疗法的临床需求未得到满足，DBM 申请了 1 期/阶段“快速通道”奖项，以加快该项目从目前的速度进入临床试验。该计划第一阶段的总体目标和里程碑包括： (a) 推进并完成先导小分子的基础药物化学衍生化； (b) 进行全面的细胞和分子作用机制（MoA）评估； (c) 在新型 PKD 小鼠模型中进行体内功效概念验证。将与约翰霍普金斯大学 PKD 中心合作，在 PKD 小鼠中施用和评估先导药物。凭借 DBM 43H11 先导药物类别已取得的第一阶段成果，计划的第二阶段里程碑旨在：(d) 完善体内“成药性”的药物化学； (e) 全面、具体地定义细胞和分子 MoA； (f) 进行 ADME/DMPK 以获得完整的临床前概况； (g) 选择主要临床候选人进行 IND 备案和 PKD 临床试验 规划。 DBM 将与约翰·霍普金斯 PKD 中心、药物化学 CRO 和 ADME/DMPK CRO 联合开发最佳临床候选药物，在未来与生物制药公司建立许可外合作伙伴关系的第 2 阶段工作中进行设想。 BM，IC。