Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors.

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.

PURPOSE: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. EXPERIMENTAL DESIGN: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). RESULTS: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. CONCLUSIONS: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR.

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

Synthesis of 3-(hetero)aryl tetrahydropyrazolo[3,4-c]pyridines by Suzuki-Miyaura cross-coupling methodology.

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.

The first intramolecular silene Diels-Alder reactions.

The synthesis of silaheterocycles through the first examples of an intramolecular silene Diels-Alder reaction is described.

The experiences of adults with learning disabilities attending a sexuality and relationship group: "I want to get married and have kids".

BACKGROUND: People with learning disabilities are frequently denied or restricted in their right to express their sexuality by restrictive policies, negative attitudes or lack of awareness of their needs. They also tend to have differing and unrecognised sexual health needs to those of the general population. Evidence suggests that acquiring a greater knowledge and awareness of sexuality and relationship issues helps to decrease these disadvantages and to promote a greater sense of well-being for this group. METHODS: The experiences of eight adults with learning disabilities attending a sexuality and relationship group, based on a mixture of validated and established sexuality and relationship programmes, were explored using a case study approach. Participants' experiences were gathered through semi-structured interviews and analysed using qualitative content analysis supported by participant observation and pre- and post-group assessment of knowledge. RESULTS: Participant experiences were unique and individual, with few shared opinions. All participants demonstrated increases in their total knowledge scores in the post-group assessment and felt that attending the group had changed their views on relationships; they felt that they were more able to talk to others, to trust someone, to feel confident to want longer relationships and to be married with children. CONCLUSIONS: Sexuality and relationship groups can offer participants a beneficial and positive experience to explore such issues. The experiences of participants could be enhanced through adopting a person-centred approach and through recognising that participants have individual experiences that may not be shared within the group environment.

Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).

A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

Acyl polysilanes: new acyl anion equivalents for additions to electron-deficient alkenes.

Silenes, generated through thermolysis of acylpolysilanes, add to alpha,beta-unsaturated esters to form cyclobutanes and silylsubstituted cyclopropanes in moderate yields. Upon Si-C bond oxidation the cyclopropanes are converted directly to 1,4-dicarbonyl compounds, thus demonstrating the formal acyl anion chemistry of acyl polysilanes.