John OveringtonEMBL-EBIjpo@ebi.ac.uk

Kinases: The Clinical Kinome and role in Neglected Disease

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

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

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.

The Clinical Kinome

Clinical Kinome

• 396 Clinical stage human kinase inhibitors– 30 Approved small molecule kinase inhibitors

• 15 -tinib – tyrosine kinase inhibitors• 7 -rolimus – mTor inhibitors• 4 -rafenib – Raf inhibitors• 2 -anib – angiogenesis inhibitors • 1 -metinib – met inhibitor• 1 -dil – Rho kinase inhibitor (Japan only)

– 36 Phase 3– 138 Phase 2– 192 Phase 1

• Phase 1:2 ratio is atypical due to many trials being phase 1/2 oncology trials

• Assembling an Open Access physical panel ca. 270 inhibitors

Kinase Inhibitors in Clinical Development

Companies Developing Kinase Inhibitors

Kinase Inhibitor Attrition

Kinase Inhibitor Attrition

USAN to approved fraction! – ~0.2 is long term mean for all drugs across all classes

Productivity By Company

n.b. Includes all inhibitors, regardless of in-/cross-licensing activity

Polypharmacology of Kinase Inhibitors

US launched

Tofacitinib Tozasertib(Ph. II)LapatinibGefitinibErlotinib

Staurosporine(no trials)

Sunitinib Sorafenib Imatinib Dasatinib

Adapted from Ghoreschi et al, Nature Immunology 10, 356 - 360 (2009)

Drug Pharmacokinetics

Imatinib, 200 mg uid

Conc

entr

ation

(ng/

mL)

Time (hr)

0

500

1000

1500

48 96 144 192 2400

• Large ‘tides’ of target exposure during dosing schedule

Filppula et al, Clin. Pharmacol & Therap (2013) 94 383-389

Extraction & Curation of PK Data

Imatinib Target Spectra

6.0

Tyrosine-protein kinase FYN 5.38ATP-binding cassette sub-family G member 2 5.39c-Jun N-terminal kinase 1 5.40Serine/threonine-protein kinase 17A 5.41c-Jun N-terminal kinase 3 5.50Dual specificity protein kinase CLK4 5.53Mixed lineage kinase 7 5.59Tyrosine-protein kinase FGR 5.62Tyrosine-protein kinase FRK 5.64Maternal embryonic leucine zipper kinase 5.72Serine/threonine-protein kinase GAK 5.72Ephrin type-A receptor 8 5.77Serine/threonine-protein kinase RAF 5.77Interleukin-1 receptor-associated kinase 1 5.92

Tyrosine-protein kinase LCK 7.00Platelet-derived growth factor receptor alpha 7.09Carbonic anhydrase 15 7.11Carbonic anhydrase IX 7.12Platelet-derived growth factor receptor beta 7.14Tyrosine-protein kinase ABL 7.20Platelet-derived growth factor receptor 7.30Discoidin domain-containing receptor 2 7.34Epithelial discoidin domain-containing receptor 1 7.37Carbonic anhydrase I 7.50Carbonic anhydrase II 7.52Tyrosine-protein kinase ABL2 7.94

Carbonic anhydrase XII 6.01Homeodomain-interacting protein kinase 4 6.02Tyrosine-protein kinase Lyn 6.05Carbonic anhydrase III 6.28Tyrosine-protein kinase BLK 6.28Carbonic anhydrase XIV 6.33BCR/ABL p210 fusion protein 6.41Carbonic anhydrase VI 6.41Phosphatidylinositol-5-phosphate 4-kinase type-2 gamma 6.42Macrophage colony stimulating factor receptor 6.54Stem cell growth factor receptor 6.62Bcr/Abl fusion protein 6.66Carbonic anhydrase VII 6.96

7.0 8.0

Imatinib 400 mg single dose from Jawhari et al (2011) J. Bioequiv. Availab. 3 161-164; Data is median pChEMBL values for human targets from ChEMBL 16

Conc

entr

ation

(ng.

ml-1

)

Time (hr)

Kinases in ChEMBL• 625 protein kinase targets• 601,895 kinase associated bioactivities

Kinases in ChEMBL

Kinases in ChEMBL

Kinase SARfari

‘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

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.

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.

SB-202190 SB-220025

SB-218078SB-203580

Insights into Selectivity/Promiscuity

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

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. Martinez-Jimenez, 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.

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

Docking of GSK1132084A into M.tb. pknB

GSK1598164A and ATP docked to active site of pknB crystal structure (3F69)

GSK1598164A ATP

Acknowledgements

Krister WennerbergPrson Gautam

Bissan Al-Lazikani Francis Atkinson Mark Davies

Gerard Van WestenGeorge Papadatos

Anne Hersey

Bill ZuercherJim Brown

Francisco Martinez-JimenezMarc Marti-Renom

cnag

http://chembl.blogspot.com