Inlighta Biosciences L.l.c.

Design of Calcium-sensing Receptor Targeted Thera(g)nostic Agents - Summary Calcium-sensing Receptor (casr), as One of the Family C G-protein-coupled Receptors (gpcrs), Largely Modulates Extracellular CA2+ by Triggering Multiple Intracellular Signaling Pathways. Casr Is Expressed in the Kidneys, Parathyroid Glands, Colon, and Other Cells, Representing Its Differential Yet Key Roles in Responding to Extracellular Calcium, Amino Acids, and Metabolites, in Different Organs. Numerous Diseases Have Been Attributed to Calcium Mishandling (e.g.,nephrolithiasis) and Secondary Hyperparathyroidism (HPT), With Over 200 Casr Mutations That Can Significantly Alter Casr Expression. There Is a Pressing Unmet Medical Need to Develop Positive Allosteric Modulators for PKD and Other Diseases With Cellular and Organ Specificity and Reduced Liver Toxicity. the Major Barriers to Developing Effective Drugs Are a Lack of Knowledge of Tempo-spatial Quantitative Expression of Casr in the Body and Its Changes During Disease Progression and Regression. We Recently Determined the First Crystal Structure of the Human Casr Extracellular Domain (ECD) With a Bound Tryptophan Derivative (TNCA) at 2.1 Å, a Potential Positive Allosteric Modulator. This Led Us to Design and Synthesize a Drug Candidate Tnca That Has Strong Agonist Activity and Specificity to Casr. the Goal of This Phase I Proposal Is to Acquire Proof-of-concept Results for Design and Generation of Tnca Analogs Having Optimal Drug Activity and Cellular Specificity as Agonists and Antagonists. in Addition, We Will Also Develop Casr Targeted Pet Agents for Renal Imaging in a Preclinical PKHD1PCK Rat Model (studies in This Model Led to Clinical Trials of an Fda-approved PKD Therapeutic). Aim 1 Is to Optimize and Determine Tnca Analogs With Best Casr Drug Activity as Agonists & Antagonists. Aim 2 Is to Perform in Vivo Mapping of Casr Distribution in PKD (PKHD1PCK) Rat Model by Micropet Imaging. Phase Ii Will Further Validate Drug Efficacy of Tnca Analogs, Imaging Capability for Casr Associated Kidney Diseases Using Animal Models, and Safety Profile for an Eind. Success in Our Proposed Studies Will Provide Essential Results for a Novel Avenue in the Development of Casr Specific Drug Candidates for the Effective Treatment of Various Casr Associated Human Diseases Using Newly Available Structures and Patented Methodology. in Addition, the Developed Pet Imaging Agents Will Enable Us to Map Casr Distribution and Heterogeneous Expression During PKD Disease Progression and Regression in Vivo, as a Companion Diagnostic for Patient Risk Stratification, and for Outcome Prediction and Novel Drug Development. We Anticipate That the Proposed Studies Will Foster the Development of Transformative Novel Markers of the Disease Activity That Will Enhance Clinical Care of PKD and Other Kidney Diseases.