The design and synthesis of small molecule bromodomain inhibitors

Previously held under moratorium in Chemistry department (GSK) from 28/02/2019 until 18/06/2021.The confidentiality statement on each page of this thesis DOES NOT applyPan-BET inhibitors show profound anti-proliferative and anti-inflammatory activity and, as such, several compounds have entered clinical trials for oncology indications. However, dose-limiting toxicities have been observed in patients which could limit their use. As the BET family consists of 4 bromodomain containing proteins (BRD2, 3, 4, and T), each of which contain 2 bromodomains (a BD1 and a BD2 domain), there is the potential that inhibitors which selectively target a single protein or domain, will retain efficacy and mitigate the dose-limiting toxicity observed with pan-BET inhibitors. This work describes the development of a series of BD2 selective 2,3-dihydrobenzofurans as highly potent BD2 inhibitors with 1000-fold selectivity over BD1. Investment in the development of two orthogonal routes delivered inhibitors which were potent and selective but had raised in vitro clearance and low solubility. An in silico Metasite prediction identified dehydrogenation of the 2,3-dihydrobenzofuran as a metabolic weakness. Insertion of a synthetically challenging quaternary centre into the 2,3-dihydrobenzofurans blocked the predicted site of metabolism and improved solubility. This led to the development of GSK852; a potent, 1000-fold selective, highly soluble compound with good in vivo rat and dog PK as a promising pre-candidate molecule. Whilst the BET family has generated much excitement in drug discovery, it contains only 8 of the 61 known bromodomains. The function of many of the non-BET bromodomains is currently unknown and there is significant interest in the development of selective chemical probes which will enable elucidation their biological roles and identify new therapeutic targets. This work also details the identification of a chemical probe for the CECR2 bromodomain. Starting from a promiscuous template, work was carried out to improve the potency, selectivity and physico-chemical properties of the chemotype. Structure based optimisation of a hydantoin lead to the development of GSK232, a highly potent, selective and soluble chemical probe for CECR2.Pan-BET inhibitors show profound anti-proliferative and anti-inflammatory activity and, as such, several compounds have entered clinical trials for oncology indications. However, dose-limiting toxicities have been observed in patients which could limit their use. As the BET family consists of 4 bromodomain containing proteins (BRD2, 3, 4, and T), each of which contain 2 bromodomains (a BD1 and a BD2 domain), there is the potential that inhibitors which selectively target a single protein or domain, will retain efficacy and mitigate the dose-limiting toxicity observed with pan-BET inhibitors. This work describes the development of a series of BD2 selective 2,3-dihydrobenzofurans as highly potent BD2 inhibitors with 1000-fold selectivity over BD1. Investment in the development of two orthogonal routes delivered inhibitors which were potent and selective but had raised in vitro clearance and low solubility. An in silico Metasite prediction identified dehydrogenation of the 2,3-dihydrobenzofuran as a metabolic weakness. Insertion of a synthetically challenging quaternary centre into the 2,3-dihydrobenzofurans blocked the predicted site of metabolism and improved solubility. This led to the development of GSK852; a potent, 1000-fold selective, highly soluble compound with good in vivo rat and dog PK as a promising pre-candidate molecule. Whilst the BET family has generated much excitement in drug discovery, it contains only 8 of the 61 known bromodomains. The function of many of the non-BET bromodomains is currently unknown and there is significant interest in the development of selective chemical probes which will enable elucidation their biological roles and identify new therapeutic targets. This work also details the identification of a chemical probe for the CECR2 bromodomain. Starting from a promiscuous template, work was carried out to improve the potency, selectivity and physico-chemical properties of the chemotype. Structure based optimisation of a hydantoin lead to the development of GSK232, a highly potent, selective and soluble chemical probe for CECR2