2. Overview
• Establishing a View of the Clinical Kinome
• Sources of Kinase SAR data
– ChEMBL and Kinase SARfari
• Community precompetitive efforts
– GSK PKIS
• Kinase inhibitors in neglected disease
– Tuberculosis HTS analysis
3. What is the Current Clinical Kinome?
• No simple way of finding out
• Classic ‘competitive intelligence’ problem
– Many commercial systems exist – expensive and closed
– No redistribution, no integration, no freedom!
• We built our own dataset
– There is a lot of interesting stuff on the internet
– PRISM – Proactive Retrieval of Interesting Structures and
Mechanisms
– Open Data
4. What is the Current Clinical Kinome?
• Phased strategy to building
– Approvals – US/Europe/Japan
– USAN/INN Process documents
– Clinical Trials (http://www.clinicaltrials.gov)
– Company pipeline documents
– Chinese compound vendors
• Focus on highest phase, chemical structure, research
codes, intended efficacy targets
– Not commercial/deal information, specific
trials, outcomes, etc.
20. ‘Full Matrix’ Kinase Datasets in
ChEMBL
• Ambit Biosciences
– 72 compounds against 442 targets
– Nature Biotechnology 2011, 29 (11), 1046-1051
• Millipore
– 158 compounds against 234 targets
– 73,944 data points
• DrugMatrix
– 860 Compounds against 132 targets
• 53 7TMs, 10 kinases, 7 P450s, 6 proteases, hERG, 54 others
– https://ntp.niehs.nih.gov/drugmatrix/index.html
• GSK Published Kinase Inhibitor Set (PKIS)
– 367 inhibitors published by GSK covering >20 chemotypes
– Measurements (so far) from 2 screening panels
• Nanosyn and UNC
21. PKIS Compound Clustering
(a) The size and diversity of the PKIS compound classes, with representative structures. The height of each bar
represents the number of compounds within each class. The segments within each indicate different compound
clusters, defined by a sphere exclusion method. Compound clustering was based upon Daylight Tanimoto
fingerprint similarity (www.daylight.com) with a cluster radius of 0.85, as outlined by Taylor 68 and applied by
Martin, Kofron and Traphagen 69. (b) Histograms of molecular weight and cLog P values for PKIS compounds.
22. Frequency of inhibition by the PKIS set
Frequency of inhibition of kinases
by the PKIS. Increasing size and
red colour of circles is related to
the number of PKIS compounds
inhibiting each kinase by 50% at
0.1 µM compound.
24. Kinase Inhibitors & Neglected Disease
• Much activity in Malaria and TB for kinase
inhibitors
– Questions over selectivity for host kinases?
• Our own work has focused on HTS
triage/target ID from a phenotypic TB screen
25. TB HTS
• GSK Tres Cantos labs
– L. Ballell, R.H. Bates, R.J. Young, D. Alvarez-Gomez, E. Alvarez-Ruiz, et
al. (2013) ‘Fueling Open-Source Drug Discovery: 177 Small-Molecule
Leads against Tuberculosis’. ChemMedChem.
– All data in http://dx.doi.org/10.6019/CHEMBL2095176
• 776 potent M.tb BCG
– 177 confirmed actives in M.tb H37Rv pathogenic strain
• Three approaches to predict targets
• Naïve Bayes models
• Docking
• Nearest neighbour
– F. nez- nez, G. Papadatos, L. Yang, I.M. Wallace, V. Kumar, U.
Pieper, A. Sali, J.R. Brown, J.P. Overington, & M.A. Marti-Renom.
(2013) ‘Target prediction for an open access set of compounds active
against Mycobacterium tuberculosis’, PLoS Comp. Biol. In press.
26. Kinases in M.Tb
• Between 4 and 20 kinases in Mycobaterium spp.
– pknA and pknB essential for M.tb viability
– pknB predicted to be target for 4 GSK compound
clusters
27. Docking of GSK1132084A into M.tb. pknB
GSK1598164A and ATP docked to
active site of pknB crystal structure
(3F69)
GSK1598164A ATP