Development of CDK4/6 Inhibitors as Novel Renal Protectants

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is common, expensive, and highly morbid. There are currently no therapies for AKI, and prevention and treatment represents a 6.3 billion market opportunity annually in the U.S. Moreover, patients are developing AKI more frequently and the number of patients that survive severe AKI is growing. Between the years of 1988 and 2002, the number of patients who survived AKI requiring dialysis increased from 2.4 to 19.4 per 100,000 population. Althoughsome patients may recover from AKI, many progress to chronic kidney disease (CKD). The proportion of AKI survivors who progress to the most severe form of CKD, end-stage renal disease, has increased over the last two decades, at an enormous societal cost.It has been estimated that caring for patients with CKD accounted for 19% of the Medicare budget in 2002. Novel therapies are urgently needed for the treatment of both AKI and CKD. G-Zero Therapeutics (GZ) is ready to meet this urgent need for effective renal protectants by leveraging intellectual property surrounding a novel therapeutic approach utilizing proprietary small molecule CDK4/6 inhibitors to induce pharmacological quiescence (PQ). GZ is developing and commercializing their novel PharmacologicalQuiescence (PQ) technology. PQ is based on the observation that many cell types are more sensitive to toxic insult when proliferating as opposed to when non-dividing (i.e. quiescent). Crucially, a few specific cell types can be rendered transiently and reversibly quiescent by treatment with small molecule inhibitors of two cyclin dependent kinases (CDK4/6). Thus, certain cells types can be protected by PQ, without the generalized toxicity (e.g. myelosuppression) of non-specific anti-mitotics. GZ has shownthat protective PQ can be induced in CDK4/6-dependent cell types at the time of insult (e.g. cytotoxic chemotherapy), and that these cells can then be released to re- enter the cell cycle and proliferate when the insultin exposure has terminated. The PQ approach has been initially used by GZ to afford protection of hematopoietic stem and progenitor cells (HSPC) within the bone marrow from the toxicity of radiation and chemotherapy. This proposal capitalizes on the recent discovery from Dr. Sharpless and Dr.Benjamin Humphreys at Harvard Medical School (a consultant on this proposal), that, like HSPC, renal epithelial cells also depend on the catalytic activity of CDK4/6 for proliferation. GZ's preliminary data show that epithelial cells in the kidney can berendered quiescent transiently by CDK4/6 inhibitors, and that this affords significant protection from renal insults such as chemotherapy and ischemia, thereby ameliorating AKI. The Phase I portion of this proposal will be accomplished in two significantaims: (1) To evaluate the in vitro efficacy and cellular toxicity of GZ proprietary small molecule CDK4/6 inhibitors as novel renal protectants. (2) To evaluate potential GZ lead candidate's ability to induce PQ in vivo in pharmacodynamic (PD) assays predictive of renal protection efficacy. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is the transient loss of kidney function due to ischemia (low blood flow to the kidney), inflammatory disease or nephrotoxicity (primarily due to the use of cytotoxic chemotherapy drugs and radio-contrast dye). Each year, millions of patients undergo cardiovascular surgery, medical imaging procedures, or cytotoxic chemotherapy, and these patients are at significant risk for AKI. AKI is common and costly, and its development is independently associated with an increased risk of death in hospital in-patients. Currently, 700,000 U.S. patients are affected annually and all suffer permanent loss of kidney function to some degree. Nearly 20% ofaffected patients develop severe AKI which can lead to multi-organ failure, sepsis and death. Novel therapies are urgently needed for the prevention and treatment AKI, since there are currently no available therapies. G-Zero Therapeutics (GZ) is ready tomeet this urgent need for effective renal protectants through the development of their proprietary small molecule CDK4/6 inhibitor series.