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A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.

A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.

A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays.

A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.

Several 2-aryl and 2-heteroaryloxazolo[4,5-b]pyridines were synthesised in high yields from zwitterion or hydroxyamidine derivatives by heating in dimethylacetamide. These intermediates were generated via hetarynic reaction with the complex base NaNH 2 -t-BuONa (5:2). The same reactions were possible with quinoline derivatives.

Unprecedented dihydrodipyridopyrazines were easily obtained by hetarynic dimerization of 2-alkylamino-3-halogenopyridines in the presence of the complex base NaNH2–tBuONa. Derivatizations of the new heterocycles are described. The anticancer activity of these compounds is also mentioned.

Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.

We describe the lithiation of the recently prepared 5,10-dimethyl-5,10-dihydrodipyrido[2,3-b:3,2-e] and [2,3-b:2,3-e]pyra-zines 1 (R=CH 3 ) and 2 (R=CH 3 ), respectively. Interestingly while 1 was metallated at the pyridinering, 2 was lithiated at the methyl groups. Reactions with electrophiles led to new functionalised dihydrodipyridopyrazines.

A macrocyclic 2-anilino-4-phenyl-pyrimidine CDK/Flt3/JAK2 inhibitor was found to have moderate PDK1 activity. After docking into a PDK1 X-ray structure it was suggested that the pyrimidine ring could be substituted for a purine thereby increasing the number of hydrophobic contacts with the protein and forming an additional hydrogen bond to the kinase hinge. Deletion of the macrocyclic linker allowed a more rapid optimisation of the aromatic substituents as well as the introduction of an amino-amide solubility tag. This improved both binding to the enzyme and physiochemical properties without compromising ligand efficiency.

3,4-Dehydroquinoline was easily generated from 3-bromoquinoline and a complex base NaNH 2 – t BuONa. Nucleophilic condensation of amines and thiolates were performed in good yields.

3,4-Dehydroquinoline was easily generated from 3-bromoquinoline and a complex base NaNH 2 – t BuONa. Nucleophilic condensation of amines and thiolates were performed in good yields.