The compounds did not inhibit the endocannabinoid hydrolases such as ABHD6, MAGL and FAAH, nor did they show appreciable activity towards the cannabinoid receptors. Activity-based protein profiling of mouse brain membrane proteome with a serine hydrolasetargeting probe revealed that the triterpenoids selectively inhibited ABHD12 with no additional targets evident among the metabolic serine hydrolases. Thus contrary to preconceived thinking, the triterpenoids showed unprecedented selectivity for ABHD12, not only over other serine hydrolases but also over cannabinoid receptors. Finally, using our SAR analysis with the presently described betulin-based compound series, we have disclosed important structural features required for ABHD12 inhibition. We have used these data in the development of the first pharmacophore model for ABHD12. This model should be useful in further studies aiming at the discovery of novel lead structures for ABHD12 inhibitors. Treatment options, however, for advanced, recurrent or metastatic ECs, are limited and consist mainly of R428 cytotoxic chemotherapy. Potential targeted treatments are under clinical investigations but have not yet been incorporated in routine clinical use. EC is a heterogeneous disease with distinct histological and molecular characteristics. So far, EC have been classified into types I and II. This is based on the different histological properties and on the clinical prognosis. In addition, distinct molecular alterations occur preferentially in either type I or type II EC. Whereas type I tumours are characterized by microsatellite instability and polymutations in different types of genes, almost all type II tumours harbour mutations of the tumour suppressor gene TP53. Recently, novel molecular subgroups have been described in a way akin to breast cancer. Based on their mutation profile and copy-number changes ECs are categorized into: the ultramutated, the hypermuted, the copy number low and the copy number high subgroup. The hypermutated subgroup includes mostly endometrioid EC, all harbouring microsatellite instability. These tumours are known to develop mutations in various other genes but also those involved in the DNA double strand break repair machinery. One of the most common recurrent mutation is found in the MRE11 gene, whose product is a part of the MRE11-RAD50-NBS1 – complex that is involved in the detection and repair of DNA double-strand breaks. MRE11 germline mutations that cause a lethal phenotype in mice are rarely encountered in humans and lead to an Ataxia telangiectasia-like disorder. Somatic mutations in MRE11, however, are frequently detected in colorectal cancers with MSI and have also been suggested for MSI-positive ECs. Mutations of the intronic poly sequence of MRE11 between exons 4 and 5 are frequent events in MSI positive colorectal und ECs. In EC, MSI is present in more than 20% of tumours and is mainly caused by epigenetic silencing of the MMR gene MLH1. This leads to changes in the number of nucleotide repeats found in coding and non-coding elements of many genes such as MRE11. Synthetic lethality occurs when two individually occurring mutations have no effect on cell viability, but cause cell death in combination. Inhibition of a synthetic lethal partner gene in cancer cells presenting a synthetic lethal mutation may prove an attractive strategy to develop specific anti-cancer drugs with minimal side effects in GSK1363089 healthy tissue. Recent studies have revealed that cancers with loss of function of BRCA1 or BRCA2 show exquisite sensitivity to Poly polymerase inhibitors. Given that MRE11 is involved in DNA DSB repair through the MRN-complex, loss of function of this complex through inactivating mutations might lead to sensitivity to PARPinhibitors.