Targeting Myosin to Treat Polycystic Kidney Disease

PROJECT SUMMARY Polycystic kidney disease (PKD) is a major life-threatening, multi-organ disorder that affects 12M individuals, representing a market opportunity of $1B. In PKD, tiny tubules in the kidneys, liver, and brain vasculature expand into fluid-filled cysts. PKD is commonly inherited as a loss-of-function mutation in PC1 (polycystin-1) or PC2, but how this results in cysts remains incompletely understood. Tolvaptan, a vasopressin receptor antagonist, is the only approved treatment, but side effects make it unsuitable for many patients. Thus a compelling need and market exists for additional treatments and targets. To better model PKD and develop therapeutic strategies, we have previously invented human organoids that recapitulate PKD-specific cyst formation from kidney tubules. Our studies revealed that inhibitors of NMII (non-muscle myosin II), an ATP-driven motor that regulates stiffness and contractility, increase cystogenesis in PKD organoids. Similarly, genetic NMII deficiency causes kidney cysts in mice in vivo. Conversely, we can now show that NMII activators reduce PKD cyst growth, both in human organoids and mice. Such NMII activators are first-in-class compounds, building on studies advancing cardiac myosin II activators into clinical trials. Our Plurexa-UW team has furthermore blueprinted a pipeline of drug development in this area, from in silico all the way to in vivo studies. Based on our studies and the literature, we hypothesize that small molecule NMII activators induce conformational changes in the NMII active site that increase ATPase activity and actinomyosin contractility in PKD tubules, inhibiting their deformation into cysts. The primary objective of this project is to sufficiently demonstrate and de-risk an NMII activator to justify advancing it into IND-enabling studies for PKD, potentially in partnership with a pharmaceutical company. A secondary goal is to advance our suite of tools in silico, in vitro and in vivo as a cohesive platform for drug development and discovery in this arena. We will achieve the goals and prove the hypothesis with two aims: Aim 1. Define the structure-activity relationship of NMII activators using a computational-biochemical pipeline suitable for lead optimization. Aim 2. Prepare NMII activators for IND-enabling studies by intervening with cyst formation in vitro and in vivo. These complementary Aims will be pursued in parallel to establish an optimally potent and selective NMII activator across biological scales. We will confer with an expert advisory council to guide the work towards establishing a basis for IND-enabling studies for these first-in-class compounds.