DBM Anti-Proliferative Lead Small Molecules for Polycystic Kidney Disease

描述（由申请人提供）：最近在DiscoveryBioMed，Inc.的基于人细胞的药物发现项目中发生了一项重要的发现和验证事件。(DBM)产生了一类领先的细胞抑制性抗增殖小分子，其显示出纳摩尔效力和针对过度增殖的人PKD细胞的显著功效，所述过度增殖的人PKD细胞在紧急的囊性肾组织内产生并形成重塑的PKD囊肿。DBM在该项目中的优势在于我们能够从正常和患病的肾脏中培养和实施原代人类细胞，以及DBM创始人在PKD领域的深厚专业知识和出版记录。DBM在药物发现和验证的关键路径中实施了这些原代人类PKD细胞系统，并将在继续的拟议工作中继续实施所述人类患病细胞平台。目前还没有PKD特异性治疗药物出现或被FDA批准。正在开发和试验中的现有PKD药物是从其他疾病项目中“重新利用”的。因此，对于PKD的小分子疗法存在显著且关键的未满足的临床需求。DBM还将这类药物视为PKD预防剂;鉴于在过去几十年中肾脏缓慢进展/增大，通过在历史上患有ADPKD的家庭中进行成像监测，针对ADPKD发展的药物将特别有效。 这种常染色体显性遗传病药物化学驱动的修饰是这类先导药物正在进行中，并已产生针对PKD和广泛癌症的纳摩尔效力，并且对囊性或癌细胞与正常细胞具有特异性。该DBM 43 H11程序针对典型的第1阶段SBIR状态进行加速。正因为如此，由于与约翰霍普金斯PKD中心的关键分包合作，以及对新PKD特异性疗法的关键未满足的临床需求，DBM申请了1期/阶段“快车道”奖，以加速该项目从目前的步伐进入临床试验。该项目第1阶段的总体目标和里程碑包括：（a）推进和完成先导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制（MoA）评估;（c）在新型PKD小鼠模型中生成概念体内疗效证明。将与约翰霍普金斯PKD中心合作，在PKD小鼠中给予和评估先导药物。有了这些已经在DBM 43 H11先导药物类别上取得进展的1期成果，计划的2期里程碑将被编写为：（d）完善体内“可药用性”的药物化学;（e）全面和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;以及（g）选择IND申报和PKD临床试验的先导临床候选药物 规划最佳临床候选药物将由DBM与约翰霍普金斯PKD中心、药物化学CRO和ADME/DMPK CRO共同开发，预计将在未来与生物制药公司建立许可证外合作伙伴关系的第2阶段工作中进行。BM，Ic.

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.