Binder Molecule Targeting the Androgen Receptor for Prostate Cancer Treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F11992719%3A_____%2F26%3AN0000002" target="_blank" >RIV/11992719:_____/26:N0000002 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Binder Molecule Targeting the Androgen Receptor for Prostate Cancer Treatment

Popis výsledku v původním jazyce

A set of small-molecule binders against the androgen receptor splice variant AR-V7 was developed as a functional sample within project TM05000031. The result addresses the need for new molecular starting points against drug-resistant prostate cancer, where AR-V7 is a clinically relevant target. The binders are intended either to directly modulate AR/AR-V7 function or to serve as warheads for future PROTAC constructs aimed at selective receptor degradation. The sample was generated through an iterative workflow integrating 1D photo-CIDNP NMR fragment screening, AI-guided virtual screening using the deepHitExplorer model, medicinal-chemistry selection, and orthogonal experimental validation by microscale thermophoresis and NMR. Across two screening rounds, 167 candidate compounds and 4 selected enantiomers were tested, of which 91 showed detectable binding to AR-V7, and at least 5 compounds reached low-micromolar affinity in the approximate range of 1–20 µM. The binders are fragment-like to lead-like molecules with molecular weight up to 400 Da, predominantly based on an indole scaffold. Their interactions with AR-V7 were further characterized by ligand-epitope mapping using 1D photo-CIDNP and by protein-observed chemical-shift perturbation analysis, providing qualitative information on binding sites and interaction patterns. The result represents an early preclinical hit series and validates the combined NMR-AI discovery workflow developed in the project. The functional sample is suitable for further medicinal-chemistry optimization toward more potent and selective AR-V7 modulators and supports future partnering, licensing, and downstream drug-development activities. Under the current cooperation framework, AnHorn Medicines (the Taiwanese partner) will have exclusivity in the future commercialization of the hit compounds.

Název v anglickém jazyce

Binder Molecule Targeting the Androgen Receptor for Prostate Cancer Treatment

Popis výsledku anglicky

A set of small-molecule binders against the androgen receptor splice variant AR-V7 was developed as a functional sample within project TM05000031. The result addresses the need for new molecular starting points against drug-resistant prostate cancer, where AR-V7 is a clinically relevant target. The binders are intended either to directly modulate AR/AR-V7 function or to serve as warheads for future PROTAC constructs aimed at selective receptor degradation. The sample was generated through an iterative workflow integrating 1D photo-CIDNP NMR fragment screening, AI-guided virtual screening using the deepHitExplorer model, medicinal-chemistry selection, and orthogonal experimental validation by microscale thermophoresis and NMR. Across two screening rounds, 167 candidate compounds and 4 selected enantiomers were tested, of which 91 showed detectable binding to AR-V7, and at least 5 compounds reached low-micromolar affinity in the approximate range of 1–20 µM. The binders are fragment-like to lead-like molecules with molecular weight up to 400 Da, predominantly based on an indole scaffold. Their interactions with AR-V7 were further characterized by ligand-epitope mapping using 1D photo-CIDNP and by protein-observed chemical-shift perturbation analysis, providing qualitative information on binding sites and interaction patterns. The result represents an early preclinical hit series and validates the combined NMR-AI discovery workflow developed in the project. The functional sample is suitable for further medicinal-chemistry optimization toward more potent and selective AR-V7 modulators and supports future partnering, licensing, and downstream drug-development activities. Under the current cooperation framework, AnHorn Medicines (the Taiwanese partner) will have exclusivity in the future commercialization of the hit compounds.

Druh

G_funk - Funkční vzorek

CEP obor

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OECD FORD obor

30401 - Health-related biotechnology

Projekt

<a href="/cs/project/TM05000031" target="_blank" >TM05000031: Zaměření na Androgenní Receptor: Vývoj Vazebných Molekul pro Léčbu Rakoviny Prostaty a Vylepšení NMR-AI Platformy pro Účinnější Návrh Léčiv.</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2026

Kód důvěrnosti údajů

C - Předmět řešení projektu podléhá obchodnímu tajemství (§ 504 Občanského zákoníku), ale název projektu, cíle projektu a u ukončeného nebo zastaveného projektu zhodnocení výsledku řešení projektu (údaje P03, P04, P15, P19, P29, PN8) dodané do CEP, jsou upraveny tak, aby byly zveřejnitelné.

Interní identifikační kód produktu

AR-V7 hit compounds

Číselná identifikace

TM05000031-V1

Technické parametry

The result is a functional sample consisting of experimentally validated small-molecule binders targeting the androgen receptor splice variant AR-V7. The compounds are fragment-like to lead-like molecules with molecular weight up to 400 Da, predominantly based on an indole scaffold. Binding to AR-V7 was confirmed by two orthogonal biophysical methods: microscale thermophoresis (MST) for affinity assessment and NMR-based assays for qualitative and semi-quantitative validation. Interaction mapping was further supported by 1D photo-CIDNP ligand-epitope analysis and 2D ^1H-^15N HSQC chemical-shift perturbation experiments. Across two screening rounds, 167 candidate compounds and 4 selected enantiomers were tested by MST, 91 showed detectable binding, and at least 5 compounds achieved low-micromolar affinity in the approximate range of 1–20 µM. The strongest binders shown in the technical documentation fall within this experimentally confirmed hit series. The result was generated through an iterative workflow combining photo-CIDNP NMR screening of 480 fragments, AI-guided prioritization using deepHitExplorer, purchase and testing of selected compounds from multi-vendor libraries, and repeated feedback retraining of the predictive model. The compounds represent an early hit series suitable for further optimization and potential use as PROTAC warheads. With respect to exploitation, the current cooperation framework assigns AnHorn Medicines the exclusive right to commercially exploit the molecules in the androgen receptor field. AnHorn is currently filing a patent application for the binder molecules.

Ekonomické parametry

The functional sample was developed cost-efficiently by screening compounds from commercially available fragment and lead-like libraries, minimizing early custom synthesis. Validation used existing consortium infrastructure, including high-field NMR, MST equipment and computational resources, so no major capital expenditure was required. The result creates economic value as a proprietary set of experimentally validated AR-V7 binders for further optimization, potential development as AR-V7 modulators or PROTAC warheads, and proof-of-concept support for commercialization of the NMR-AI platform. The target indication, drug-resistant prostate cancer, is a high-value therapeutic area. Under the current cooperation framework, commercial exploitation of the compounds is controlled by AnHorn. At this stage, the result is mainly a strategic R&D asset and technology proof of concept rather than a direct revenue-generating product.

Kategorie aplik. výsledku dle nákladů

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IČO vlastníka výsledku

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Název vlastníka

AnHorn Medicines

Stát vlastníka

CN - Čínská lidová republika

Druh možnosti využití

A - K využití výsledku jiným subjektem je vždy nutné nabytí licence

Požadavek na licenční poplatek

A - Poskytovatel licence na výsledek požaduje licenční poplatek

Adresa www stránky s výsledkem

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