# Small Molecule KLF15 Agonists for Kidney Disease

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2024 · —

## Abstract

The Centers for Disease Control and Prevention estimates more than 15% of adults in the United
States, over 30 million Americans have chronic kidney disease (CKD). Podocytes are epithelial cells in the
glomerulus whose major function is the maintenance of the kidney filtration barrier to prevent CKD.
Furthermore, the prevalence of CKD in the Veteran population is a third higher than in the general population.
Podocyte injury is implicated in diseases such as Focal Segmental Glomerular Sclerosis (FSGS). In these
diseases, the podocyte loses characteristic morphologic features and the functional capacity to maintain the
glomerular filtration barrier. In several recent studies, we reported the essential role of Krüppel-Like Factor 15
(KLF15), a kidney-enriched transcription factor, in maintaining podocyte actin cytoskeleton under cell stress.
For instance, loss of function studies in preclinical proteinuric murine models demonstrated that KLF15 is
required to prevent podocyte injury and the salutary benefits of glucocorticoids (GCs), the most common
treatment for primary glomerulopathies, are mediated by KLF15. As well, the responsiveness to GCs in human
primary glomerulopathies is associated with podocyte-specific expression of KLF15. Furthermore, induction of
human KLF15 in podocytes attenuated kidney injury in proteinuric murine models, without the adverse
sequelae of GCs. Collectively, these preclinical and clinical studies on the renoprotective effects of KLF15
induction motivated us to identify novel small molecule KLF15 agonists for kidney disease.
 We initially generated and conducted a cell-based high-throughput screening (HTS) to screen small
molecules that induce KLF15 activity. Subsequent dose-escalating studies identified novel lead compounds
with a half maximal effective concentration (EC50), in the optimal therapeutic window, required to induce KLF15
activity. Based on EC50 and druggability, we conducted Structure-Activity Relationship (SAR) on the lead
compound K-7 and generated 16 lead analogues, of which BT501, BT502, BT503, BT514, and BT412 induced
KLF15 promoter activity with or without cell stress. We also performed intial pharmacokinetic studies for K-7 in
mice and also showed that human podocytes treated with K-7 and lead analogues attenuated podocyte injury
in the setting of cell stress. Furthemore, RNA-seq of K-7 treated human podocytes shows inhibition of pathway
IL-17RA-mediated actin cytoskeleton destabilization, thereby providing the rationale to utilize a mechanistic
approach to optimize selectivity of KLF15 agonists. Finally, we observed that K-7 attenuated albuminuria and
restored podocyte markers in a preclinical proteinuric murine model. Based on these compelling preliminary
data and strong scientific rigor of prior research, we hypothesize that optimization of lead KLF15 agonists in
preclinical studies will serve as a key therapeutic in proteinuric kidney diseases. We propose to test our
hypothesis by (1) improving...

## Key facts

- **NIH application ID:** 10767771
- **Project number:** 5I01BX005300-04
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** Sandeep K Mallipattu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767771

## Citation

> US National Institutes of Health, RePORTER application 10767771, Small Molecule KLF15 Agonists for Kidney Disease (5I01BX005300-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10767771. Licensed CC0.

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