Brian Dymock

Structure-based optimization of morpholino-triazines as PI3K and mTOR inhibitors

A virtual screen of our in-house database using various fingerprint techniques returned several triazine hits which were found to be mTOR inhibitors with a slight selectivity over PI3Kα. Using structure-guided lead optimization the inhibitory activity towards mTOR and PI3Kα was increased to the low nanomolar range. Exploiting shape differences in the binding-site allowed for the design of mTOR selective inhibitors. Focus on ligand efficiency ensured the inhibitors retained a low molecular weight and desirable drug-like properties.

2-anilino-4-aryl-8H-purine derivatives as inhibitors of PDK1.

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.

Structure-based design of PDK1 inhibitors.

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.

Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening.

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.

CHAPTER 5:Designed Macrocyclic Kinase Inhibitors

Cancer continues to present as an increasing and serious global unmet medical need in todays aging population.1 Macrocyclic kinase inhibitors have reached advanced clinical testing and are making an impact in oncologic conditions including myelofibrosis, lymphomas and leukemias. Rheumatoid arthritis (RA) is also beginning to be impacted with the first macrocycle having entered Phase I clinical evaluation in healthy volunteers. Increasing reports of innovative macrocycles in preclinical research are appearing in the literature. Desirable, selective, multi-kinase inhibitory profiles against specific kinases known to be abrogated in cancer, RA, and other diseases have been achieved in a first generation series of clinical stage compact small molecule macrocyclic kinase inhibitors. Herein we discuss their design, synthesis, structure activity relationships and assessment of the latest clinical data in a range of oncologic conditions. Macrocyclic kinase inhibitors have the potential to offer new hope to patients and their families.