DBM Anti-Proliferative Lead Small Molecules for Polycystic Kidney Disease

描述(由申请人提供)：最近在DiscoveryBioMed公司(DBM)基于人类细胞的药物发现计划中发生了一项重要的发现和验证事件，产生了一类领先的细胞抑制抗增殖小分子，这些小分子显示出纳摩尔效力，并对在新出现的囊性肾组织中产生和排列重塑的PKD囊的人类PKD细胞具有显著的疗效。DBM对这一计划的优势在于我们能够培养和实施来自正常和疾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出版记录。DBM在药物发现和验证的关键路径上实施了这些主要的人类PKD细胞系统，并将在继续拟议的工作中继续实施所述人类疾病细胞平台。到目前为止，还没有出现针对PKD的疗法，也没有得到FDA批准的疗法。正在开发和试验的现有PKD药物在其他疾病项目中被重新使用。因此，对于PKD的小分子疗法仍有重要且严重的临床需求未得到满足。DBM还将这种药物类别视为PKD的预防药物；考虑到几十年来肾脏的缓慢进展/增大，通过家族内的成像监测，一种针对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指这种先导药物类别正在进行中，已经产生了对抗PKD和广泛范围的癌症的纳摩尔效力，并且对囊性细胞或癌细胞与正常细胞相比具有特异性。此DBM 43H11程序针对典型的阶段1 SBIR状态进行了加速。正因为如此，由于与约翰·霍普金斯PKD中心的关键分包合作，以及对新的PKD特定疗法的关键临床需求未得到满足，DBM申请了第一阶段/第二阶段“快速通道”奖，以加快该计划从目前的步伐进入临床试验。该计划第一阶段的总体目标和里程碑包括：(A)推进和完成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制(MOA)评估；以及(C)在一种新的PKD小鼠模型中产生体内疗效的概念证明。将与约翰霍普金斯大学PKD中心合作，在PKD小鼠身上管理和评估铅药物。鉴于DBM 43H11先导药物类别的这些第一阶段成就已经取得进展，计划中的第二阶段里程碑的脚本是：(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(S)；(F)进行ADME/DMPK以了解完整的临床前情况；以及(G)选择IND备案和PKD临床试验的主要临床候选者 计划。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，在设想的第二阶段努力中，未来将与一家生物制药公司建立非许可合作伙伴关系。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.