USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF.

Background: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts.

Methods: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells.

Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors.

Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography.

Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.

Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts.

Total synthesis of (+)-pleuromutilin.

The first enantiospecific total synthesis of the antibacterial natural product (+)-pleuromutilin has been achieved. The approach includes the synthesis of a non-racemic cyclisation substrate from (+)-trans-dihydrocarvone, a highly selective SmI2-mediated cyclisation cascade, an electron transfer reduction of a hindered ester, and the first efficient conversion of (+)-mutilin to the target.

Mechanistic studies into amine-mediated electrophilic arene borylation and its application in MIDA boronate synthesis.

Direct electrophilic borylation using Y(2)BCl (Y(2) = Cl(2) or o-catecholato) with equimolar AlCl(3) and a tertiary amine has been applied to a wide range of arenes and heteroarenes. In situ functionalization of the ArBCl(2) products is possible with TMS(2)MIDA, to afford bench-stable and easily isolable MIDA-boronates in moderate to good yields. According to a combined experimental and computational study, the borylation of activated arenes at 20 °C proceeds through an S(E)Ar mechanism with borenium cations, [Y(2)B(amine)](+), the key electrophiles.

Simple inexpensive boron electrophiles for direct arene borylation.

Electrophilic direct borylation is facilitated, and arene substrate scope enhanced, by using electrophiles derived from inexpensive reagents; specifically an amine, BCl(3) and AlCl(3).

A stereoselective, Sm(II)-mediated approach to decorated cis-hydrindanes: synthetic studies on faurinone and pleuromutilin.

The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI(2)-mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin.

Preparation of silyl substituted crotylzinc reagents and their highly diastereoselective addition to carbonyl compounds.

Readily prepared beta-silyl substituted crotylzinc reagents undergo highly selective allylation of carbonyl compounds leading to syn-homoallylic alcohols.

The participation of alkynylboronates in inverse electron demand [4 + 2] cycloadditions: a mechanistic study.

The participation of alkynylboronates in [4 + 2] cycloadditions has been investigated using both kinetic and DFT studies. Kinetic studies of the cycloaddition of tetrazine 1 with alkynylboronate 2 strongly suggest that a concerted cycloaddition mechanism is in operation. This mechanism has been confirmed by DFT calculations; moreover, a highly synchronous transition state appears to operate in this process.

A novel approach to functionalised pyridazinone arrays.

A series of 3,6-dichloro-1H-pyridazin-4-ones have been prepared via the cycloaddition of 3,6-dichlorotetrazine with alkynylboronates, and their employment as useful synthetic intermediates was highlighted through a selection of highly regioselective C-O, C-S and C-C bond forming reactions.