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-11643394-B2
Publication Date
2023-05-09
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 for the prevention and treatment of disorders associated with KLF15 signaling dysfunction, including kidney disease (e.g., chronic kidney disease), heart disease, obesity, and neurodegenerative disorders such as 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). The disclosed compounds have specific chemical structures with defined substituents and can be formulated into pharmaceutical compositions comprising an effective amount of the compound and a pharmaceutically acceptable carrier.
The problem addressed stems from the lack of novel therapeutics that significantly impact the prevention and treatment of kidney diseases, particularly glomerular diseases such as FSGS (Focal Segmental Glomerulosclerosis) and HIV-associated nephropathy. Podocyte injury is central to the etiology of chronic kidney disease (CKD) and current treatments, primarily glucocorticoids, present challenges including variable patient responsiveness and systemic adverse effects due to prolonged use. Though KLF15 is identified as a critical mediator in maintaining podocyte integrity and preventing kidney fibrosis, development of KLF15 agonists as therapeutic agents has been elusive.
This invention discloses the identification and use of small molecule KLF15 agonists to specifically activate KLF15 signaling, thereby restoring podocyte health, attenuating kidney injury, and treating associated disorders. The approach includes high-throughput screening assays in human podocytes, lead optimization using medicinal chemistry guided by structure-activity relationships (SAR), in vitro and in vivo efficacy testing, pharmacokinetic profiling including radiolabeling for PET imaging, and development of pharmaceutical compositions and kits. Additionally, it offers methods for using these compounds alone or in combination with glucocorticoids to treat disorders related to KLF15 dysfunction, aiming to improve therapeutic effects while reducing glucocorticoid-associated systemic toxicity.
Claims Coverage
The patent contains one independent claim focusing on a compound with a defined chemical structure and related pharmaceutical compositions.
Compound structure with specific substituents
A compound having a defined chemical structure as per the disclosed formulae, including specific options for substituents such as Q1, Q2, R1, R4, and others, with particular provisos on groups present under certain structural forms.
Pharmaceutical composition including the compound
Pharmaceutical compositions comprising an effective amount of the claimed compound and a pharmaceutically acceptable carrier suitable for administration.
The claims concentrate on novel small molecule compounds with defined structural features that modulate KLF15 signaling and pharmaceutical compositions comprising these compounds, providing the basis for therapeutic applications in diseases related to KLF15 dysfunction.
Stated Advantages
Utilization of small molecules to induce the expression of a pro-differentiation transcription factor (KLF15) in kidney disease is conceptually innovative.
Incorporation of combinatorial therapy by combining KLF15 agonists and glucocorticoids early in pre-IND studies maximizes therapy effectiveness and optimizes lead compounds.
Use of human podocyte-based high-throughput screening (HTS) to identify novel small molecule KLF15 agonists is novel and enhances drug discovery for glomerular disease.
Lead-optimization strategy involving iterative medicinal chemistry combined with Limited Rational Design (LRD) enables identification of selective KLF15 analogues with low nanomolar affinity efficiently.
Augmenting in vivo pharmacokinetic profiling through radiolabeling and PET imaging allows assessment of biodistribution and optimal dosing of KLF15 analogues.
Implementation of novel assays such as ELISA-like solid phase binding and surface plasmon resonance enhances selectivity optimization of KLF15 agonists via IL-17RA activity assessment.
Utilization of human kidney organoids with single-cell RNA sequencing improves preclinical model rigor for lead compound evaluation.
Preliminary structure activity relationship (SAR) studies guide the synthesis of novel KLF15 analogues with improved activity and safety profiles.
Documented Applications
Treatment of disorders associated with KLF15 signaling dysfunction including kidney disease, particularly chronic kidney disease.
Treatment of 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).
Use in restoring podocyte health and attenuating kidney injury in proteinuric murine preclinical models such as lipopolysaccharide (LPS)-induced injury and anti-glomerular antibody models.
Combination therapy with glucocorticoids to reduce systemic toxicity while maintaining therapeutic efficacy in glomerular diseases.
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