Focal adhesion kinase (FAK) is ak ey mediator of tumour progression and metastasis.T od ate,c linical trials of FAKi nhibitors have reported disappointing efficacy for oncology indications.W er eport the design and characterisation of GSK215, ap otent, selective,F AK-degrading Proteolysis Targeting Chimera (PROTAC)b ased on ab inder for the VHL E3 ligase and the knownF AK inhibitor VS-4718. Xray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice,asingle dose of GSK215 induced rapid and prolonged FAKd egradation, giving al ong-lasting effect on FAKl evels ( % 96 h) and am arked PK/PD disconnect. This tool PROTACmolecule is expected to be useful for the study of FAK-degradation biology in vivo,a nd our results indicate that FAKd egradation may be ad ifferentiated clinical strategy versus FAKi nhibition for the treatment of cancer.

The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.

The [4+2] cycloaddition of 3-alkoxyfurans with N-substituted maleimides provides the first general route for preparing endo-cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead-like properties for medicinal chemistry programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels–Alder reaction.

A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays. KEYWORDS: Interleukin-2 inducible tyrosine kinase, Itk, kinase inhibitors, aminobenzothiazole, template hopping, kinase selectivity I nterleukin-2 inducible tyrosine kinase (Itk) is a nonreceptor protein tyrosine kinase that is expressed in T cells, mast cells, and NK cells. Itk plays an important role in signaling, downstream of the T cell receptor in response to antigen presentation by MHC proteins, and its inhibition leads to reduced levels of key inflammatory cytokines. 1 In vivo experiments with Itk knockout mice suggest a role for Itk inhibitors in the treatment of asthma. 2 A number of Itk inhibitor series have been disclosed in the literature with a focus on achieving broad kinase selectivity as well as good levels of cellular activity; both of which have been relatively challenging for this tyrosine kinase. 3−6 Despite these publications, there have been no reports of an Itk inhibitor entering clinical trials and hypotheses regarding its clinical potential remain untested. 7 In-house cross screening resulted in the identification of a series of aminopyrazoles as inhibitors of Itk. This series was of particular interest to us as, in contrast to previous series investigated, compounds in this series displayed a promising level of ligand efficiency (LE = 0.36, compound 1). 8 An initial X-ray crystal structure of compound 1 (Figure 1) in Itk confirmed the aminopyrazole group was binding to the hinge region of Itk and utilizing a three-point hinge binding motif. Initial optimization work focused on the pyrimidine 2-position and the pendant group of the pyrazole. However, these modifications did not produce compounds with the desired 100-fold selectivity margin over key kinases, namely, LCK, AurA, and AurB. Compound 2 (Figure 1) represents the best combination of potency and selectivity achieved with this series. Substantial SAR knowledge had been built up around the other parts of the template at this stage, and it was hypothesized that replacing the aminopyrazole motif with an inherently more selective hinge-binder could be an efficient method of accessing novel and selective Itk inhibitors.A robust Itk crystallography system was not available at this time, and therefore a fragment based approach 9−11 using crystallography to identify new hinge-binding groups was not