T-BAP
Financiado
Targeting the Polycomb Machinery in BAP1-related Pathologies
BAP1-related mutations are common genetic lesions of several cancers and neurodevelopmental disorders (NDDs). BAP1 is a deubiquitinase that removes the repressive mono-ubiquitination at histone H2AK119 (H2Aub1) deposited by the Po...
BAP1-related mutations are common genetic lesions of several cancers and neurodevelopmental disorders (NDDs). BAP1 is a deubiquitinase that removes the repressive mono-ubiquitination at histone H2AK119 (H2Aub1) deposited by the Polycomb Repressive Complex 1 (PRC1) by associating with several regulatory subunits to form the Polycomb Repressive Deubiquitinase (PR-DUB) complex.
BAP1 inactivating mutations represent a hallmark in Malignant Mesothelioma (MM) for which genetic models proved its oncogenic role. Mutations further extend to several other cancers, also involving other essential PR-DUB regulatory subunits. This makes PR-DUB inactivation a major oncogenic event with ~40k new diagnosis each year between EU and US for which no precision therapeutic approaches exist.
The work of my Dissect-PcG ERC project found that the major role of BAP1 is to counteract H2Aub1 diffusion across the entire chromatin. This preserves chromatin plasticity enhancing Polycomb-mediated control of transcriptional identity, which is decommissioned when BAP1 is inactivated and oncogenic H2Aub1 accumulates. We also found that diffused H2Aub1 is controlled by a specific form of PRC1 - namely PRC1.3/5 - immediately suggesting a strategy to correct the effects of BAP1-related mutations. Indeed, we found that specific PRC1.3/5 loss restored normal H2Aub1 levels while compromising MM cells viability, demonstrating the therapeutic potential of targeting this non-essential arm of PRC1 repressive machinery.
By building a multidisciplinary team, the T-BAP project aims to develop compounds that can target PRC1.3/5 in living cells. We propose to use PRC1.3/5 structural data to identify specific binders that can function as warheads for the development of PROTAC degraders. This will generate a new class of molecules for the development of therapeutic strategies that can aid oncological patients with BAP1-related mutations, with a further potential application in specific NDD syndromes.
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Duración del proyecto: 18 meses
Fecha Inicio: 2023-12-06
Fecha Fin: 2025-06-30
Fecha Fin: 2025-06-30
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-12-06
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2022-POC2:
ERC PROOF OF CONCEPT GRANTS2
Cerrada
hace 2 años
Presupuesto
El presupuesto total del proyecto asciende a
150K€
Líder del proyecto
ISTITUTO EUROPEO DI ONCOLOGIA SRL
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5