Richard William Arthur Luke

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC50 ∼ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2+ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. Mol Cancer Ther; 11(4); 873–87. ©2012 AACR.

Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases.

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

Synthesis of cytidine ribonucleotides by stepwise assembly of the heterocycle on a sugar phosphate.

Although various syntheses of the nucleic acid bases exist and ribose is a product of the formose reaction, no prebiotically plausible methods for attaching pyrimidine bases to ribose to give nucleosides have been described. Kinetic and thermodynamic factors are thought to mitigate against such condensation reactions in aqueous solution. This inability to produce pyrimidine nucleosides and hence nucleotides is a major stumbling block of the “RNA World” hypothesis and has led to suggestions of alternative nucleic acids as evolutionary precursors to RNA. Here, we show that a process in which the base is assembled in stages on a sugar phosphate can produce cytidine nucleotides. The sequential action of cyanamide and cyanoacetylene on arabinose‐3‐phosphate produces cytidine‐2′,3′‐cyclophosphate and arabinocytidine‐3′‐phosphate.

Thermally cleavable safety-catch linkers for solid phase chemistry

Safety-catch linkers based on the sulfoxide/selenoxide syn elimination have been developed. Clean and efficient oxidation of the sulfide to the sulfoxide was achieved with the homogeneous oxidising system comprising of hexafluoroisopropanol (HFIP) and hydrogen peroxide. Elimination of the sulfoxide was only possible with the most activated of substrates, while the selenoxide underwent cleavage under much milder conditions.

Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.

The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.

‘One-pot’ methylation of Fmoc amino acids☆

Abstract We report here a convenient method for the conversion of Fmoc amino acids to their N-methylated derivatives. The method involves reaction with formaldehyde and then reduction with triethylsilane (TES). The method is particularly attractive in that the alkylation and reduction are carried out in situ and the reaction sequence and purification of product can readily be carried out in one day. A further advantage is that the method is not restricted to α-amino acids.

Acetoacetoxy ethyl methacrylate (AAEM) resin, a new scavenger for primary amines in the presence of secondary amines

Preliminary results on a new type of polymer scavenger, acetoacetoxy ethyl methacrylate (AAEM) resin, are reported. AAEM resin can selectively remove primary amines in the presence of secondary amines. Its application in a solution library synthesis is demonstrated.

Improving resins for solid phase synthesis: incorporation of 1- 2-(2-methoxyethoxy)ethoxy -4-vinyl-benzene

Abstract The preparation, characterisation and application of a series of non-grafted polystyrene (PS) resins containing a styrenic methoxypoly(ethylene glycol) (MPEG) derivative is presented. These novel PS-MPEG resins were designed to balance swelling and solvation with improved handling. The monomer, 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene, contained an inert phenyl ether linkage designed to provide broad chemical compatibility and stability, yet imparting all the favourable properties of the PEG group into the new resin, whilst maintaining a high loading capacity. The synthetic performance of the new resins compared very favourably to those of TentaGel™, ArgoGel™ and aminomethyl PS.

Synthesis and reactions of N,N-bis[1-(trimethylsiloxy)alkyl]-formamides: preparation of (±)-argemonine and (±)-norargemonine

Symmetrical and unsymmetrical N,N-bis[1-(trimethylsiloxy)alkyl]formamides are prepared and their reactions investigated, including an application to the synthesis of the pavine alkaloids (±)-argemonine and (±)-norargemonine

Chirally templated boronic acid Mannich reaction in the synthesis of optically active α-amino acids

Adducts from diastereoselective Mannich-type reactions of aldehydes, 2-furylboronic acid and the chiral amine template (S)-5-phenylmorpholin-2-one, have been used in the synthesis of a series of enantiomerically pure D-α-amino acids.