Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo
- 1Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences
Abstract
Dysregulation of insulin-like growth factor (IGF) signaling contributes to diverse human diseases. Therapeutic strategies have largely targeted the IGF-1 receptor, but the complexity of the IGF system has limited their clinical efficacy. Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloproteinase that regulates local IGF signaling through proteolytic cleavage of IGF-binding proteins (IGFBPs) and represents an attractive therapeutic target. Here, we report the first synthetic PAPP-A inhibitors designed to target the enzyme active site using an IGFBP-5-derived anchor sequence. Replacing the scissile bond with phosphinate or phosphonate moieties yielded potent and selective PAPP-A inhibitors. Cryo-electron microscopy revealed the molecular basis of inhibition and key active-site interactions. The compounds inhibited cleavage of IGFBP-4 and IGFBP-5, two physiological PAPP-A substrates. They suppressed IGF-1 signaling in A549 lung cancer cells, with efficacy comparable to the endogenous PAPP-A inhibitor stanniocalcin-1. They also inhibited Papp-aa-dependent IGF signaling and cell proliferation in wild-type and stc1a-/- mutant zebrafish in vivo in a dose-dependent manner. Together, these findings establish the first class of synthetic, selective PAPP-A inhibitors capable of modulating IGF signaling. They provide new chemical tools for studying and modulating pathological IGF signaling and offer new directions for developing PAPP-A-targeted therapeutic strategies.
Related
- Epigenetic repression of oncogenic signaling defines immune-permissive tumor states associated with response to immune checkpoint inhibitors in advanced NSCLC
- Positive Allosteric Modulation of mGlu and Muscarinic Receptors Differentially Regulate Nitric Oxide-Dependent Signaling in a Scopolamine-Induced Model of Cognitive Impairment
- Targeting Integrins in Triple Negative Breast Cancer: Therapeutic Potential of Monoclonal Antibodies, PARP Inhibitors, Synthetic Peptides, and Aptamers
- Prediction of late-pregnancy pelvic floor dysfunction: a nomogram model based on proton density fat fraction and synthetic magnetic resonance imaging
- Genetic Variation, Iron Status, and FGF23 Signaling Converge to Regulate Renal Calcium Buffering in Sickle Cell Disease
BibTeX
@misc{kertisova2026synthetic,
title = {{Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo}},
author = {A. Kertisova and S.-W. Shih and N. S. Kirk and J. Picha and A. Rucklova and J. Kozak and K. Mrzilkova and M. Lubos and E. Tloustova and M. Budesinsky and C. Duan and J. Jiracek and I. Selicharova},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755852},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo
AU - A. Kertisova
AU - S.-W. Shih
AU - N. S. Kirk
AU - J. Picha
AU - A. Rucklova
AU - J. Kozak
AU - K. Mrzilkova
AU - M. Lubos
AU - E. Tloustova
AU - M. Budesinsky
AU - C. Duan
AU - J. Jiracek
AU - I. Selicharova
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755852
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755852v1
AB - Dysregulation of insulin-like growth factor (IGF) signaling contributes to diverse human diseases. Therapeutic strategies have largely targeted the IGF-1 receptor, but the complexity of the IGF system has limited their clinical efficacy. Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloproteinase that regulates local IGF signaling through proteolytic cleavage of IGF-binding proteins (IGFBPs) and represents an attractive therapeutic target. Here, we report the first synthetic PAPP-A inhibitors designed to target the enzyme active site using an IGFBP-5-derived anchor sequence. Replacing the scissile bond with phosphinate or phosphonate moieties yielded potent and selective PAPP-A inhibitors. Cryo-electron microscopy revealed the molecular basis of inhibition and key active-site interactions. The compounds inhibited cleavage of IGFBP-4 and IGFBP-5, two physiological PAPP-A substrates. They suppressed IGF-1 signaling in A549 lung cancer cells, with efficacy comparable to the endogenous PAPP-A inhibitor stanniocalcin-1. They also inhibited Papp-aa-dependent IGF signaling and cell proliferation in wild-type and stc1a-/- mutant zebrafish in vivo in a dose-dependent manner. Together, these findings establish the first class of synthetic, selective PAPP-A inhibitors capable of modulating IGF signaling. They provide new chemical tools for studying and modulating pathological IGF signaling and offer new directions for developing PAPP-A-targeted therapeutic strategies.
ER -