Krüppel-like factor 15 (KLF15) small molecule agonists in kidney disease
Inventors
Mallipattu, Sandeep • Das, Bhaskar
Assignees
Icahn School of Medicine at Mount Sinai • US Department of Veterans Affairs • Research Foundation of the State University of New York
Publication Number
US-12269803-B2
Publication Date
2025-04-08
Expiration Date
2041-04-29
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Abstract
The present disclosure is concerned with small molecule modulators of KLF15 signaling useful for treating various disorders such as, for example, kidney disease (e.g., chronic kidney disease), heart disease, obesity, or a neurodegenerative disorder (e.g., amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, spinal muscular atrophy, traumatic brain injury, vascular dementia, Huntington's disease, mental retardation, and attention deficit and hyperactivity disorder (ADHD)). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to small molecule modulators of Krüppel-Like Factor 15 (KLF15) signaling useful for treating disorders associated with KLF15 signaling dysfunction such as kidney disease (e.g., chronic kidney disease), heart disease, obesity, and neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, spinal muscular atrophy, traumatic brain injury, vascular dementia, Huntington's disease, mental retardation, and attention deficit and hyperactivity disorder (ADHD). These compounds are designed to modulate KLF15 signaling by activating KLF15 or restoring its expression, often impaired in such diseases.
The problem addressed stems from a major medical need in the treatment of chronic kidney disease (CKD) and other podocytopathies. CKD is a leading risk factor for cardiovascular disease with large patient burden, especially among U.S. Veterans. Podocyte injury is central to glomerular diseases such as Focal Segmental Glomerulosclerosis (FSGS). Despite advances in understanding podocyte biology and the role of KLF15, there is a lack of novel therapeutics capable of significantly preventing or treating these diseases. Current standard treatments like glucocorticoids (GCs) have limitations, including prolonged treatment duration, systemic toxicities, and variable patient responsiveness. Thus, development of KLF15 agonists as targeted therapeutics remains elusive and highly needed.
The invention discloses small molecules with specific chemical structures that act as KLF15 agonists to modulate KLF15 signaling in vivo and in vitro. These compounds were identified and optimized through high-throughput screening (HTS) assays using human podocyte-based models, followed by structure-activity relationship (SAR) studies and medicinal chemistry to enhance potency, selectivity, and pharmacokinetic (PK) properties. Lead compounds (e.g., K-7 and analogues) have demonstrated efficacy in preclinical models by restoring podocyte differentiation markers, improving kidney function, attenuating albuminuria, and reducing fibrosis without the systemic toxicities associated with chronic GC use. Furthermore, combined treatments with glucocorticoids and KLF15 agonists show synergistic effects, allowing reduction of GC doses. The invention also proposes methods including radiolabeling and PET imaging to optimize PK profiling and biodistribution of these compounds.
Claims Coverage
The patent contains one independent chemical composition claim that defines the compounds structurally, and claims relating to pharmaceutical compositions containing these compounds and their use in treatment methods.
Compounds having defined KLF15 agonist chemical structures
Compounds are defined by specific chemical structural formulas with detailed substituent groups at various positions. These structures include precise definitions of substituents such as alkyl, halogen, amino, hydroxyl, boron-containing moieties, and requirements pertaining to particular substituent relationships and exceptions to genera.
Pharmaceutical compositions containing KLF15 agonists
Pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier are claimed for therapeutic use.
Methods for treating disorders associated with KLF15 signaling dysfunction
Methods of treating disorders such as kidney disease, heart disease, obesity, and neurodegenerative disorders by administering an effective amount of the disclosed compounds to a subject in need thereof are claimed.
Methods for modifying KLF15 signaling in a subject or cell
Methods comprising administering or contacting a subject or cell with an effective amount of disclosed compounds to activate or modify KLF15 signaling.
Kits comprising KLF15 agonist compounds
Kits comprising at least one disclosed compound and elements such as agents related to treatment, glucocorticoids, and instructions for treating disorders associated with KLF15 signaling dysfunction are claimed.
The claims primarily cover structurally defined small molecule KLF15 agonists, pharmaceutical compositions comprising them, their therapeutic applications in KLF15-related disorders, methods for modifying KLF15 signaling in subjects or cells, and kits containing the compounds and treatment-related materials. The inventive features focus on specific chemical scaffolds and their use in the prevention and treatment of diseases linked to KLF15 signaling dysfunction.
Stated Advantages
Utilization of small molecules to induce the expression of a pro-differentiation transcription factor (KLF15) in kidney disease is conceptually innovative.
Combination therapy using KLF15 agonists with glucocorticoids reduces cumulative glucocorticoid doses, maximizing therapeutic effectiveness and minimizing toxicity.
Human podocyte-based high-throughput screening enables identification of novel small molecule KLF15 agonists, offering a new approach in glomerular disease research.
An innovative lead-optimization strategy involving iterative medicinal chemistry combined with Limited Rational Design (LRD) efficiently identifies selective KLF15 agonists with low nanomolar potency.
Radiotracer labeling and PET imaging are employed to augment in vivo pharmacokinetic profiling, facilitating optimization of dosing and biodistribution.
Novel assays such as ELISA-like solid phase binding and surface plasmon resonance enhance selectivity optimization of KLF15 agonists by targeting IL-17RA.
The use of human kidney organoids coupled with single-cell RNA sequencing improves the rigor of preclinical testing for lead KLF15 agonist optimization.
Documented Applications
Treatment of disorders associated with KLF15 signaling dysfunction including kidney disease (such as chronic kidney disease), heart disease, obesity, and neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, spinal muscular atrophy, traumatic brain injury, vascular dementia, Huntington's disease, mental retardation, and ADHD.
Use as KLF15 signaling modulators in subjects or cells to treat or modify KLF15-related pathological conditions.
Combination therapy to reduce glucocorticoid dosage in the treatment of primary glomerulopathies and proteinuric diseases.
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