DBM Anti-Proliferative Lead Small Molecules for Polycystic Kidney Disease

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 thatdisplay 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 theJohns 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. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: DiscoveryBioMed, Inc. (DBM) wishes to capitalize on the discovery of a potent lead class of cytostatic anti- proliferative small molecules as clinical candidate drugs to attenuate or block the initial hyperproliferative phases of autosomal dominant and autosomal recessive polycystic kidney disease (PKD). PKD is of particular scientific interest to the Founder of DBM who has studied the basic science of this chronic hyperproliferative disorder for over 10 years. DBM is also a partner within the Johns Hopkins PKD Center, a subcontracted collaborator in this PKD drug discovery and development program. As such, we see this lead drug validation and progression program as a personal crusade for the company to offer a new therapeutic for PKD in the near future. There are no PKD-specific therapeutics that have emerged at present; thus, we seek 'Fast Track' funding to accelerate our collective effects to develop a drug in haste that was discovered in a human PKD cell platform, that is potent and specific to hyperproliferative cells without affecting normal cells, and that is viable for BioPhara partnership and for rapid entrance into clinicaltrials.