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What Lessons Can We Learn from 20 Years of Chemokine T D Di ? Receptor

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What Lessons Can We Learn from 20 Years of Chemokine T D Di ? Receptor What lessons can we learn from 20 years of chemokine receptdtor drug discovery? John G. Cumming, PhD 5th RSC / SCI symposium on GPCRs in Medicinal Chemistry 15th-17th September 2014, Actelion, Allschwil, Basel, Switzerland Outline Background: chemokines and their receptors Chemokine receptor drug discovery and development Emerging opportunities for chemokine drug discovery Conclusions and learning Chemokines and chemokine receptors CXC(α) • Chemokines (chemoattractant cytokines) are 70-120 aa proteins • 44 chemokines in 4 major families and 22 chemokine receptors in human genome • ‘Cell positioning system’ in the body • Many receptors bind multiple ligands • Many ligands bind multiple receptors Chemotaxis Human monocytes + CCL2 (red) Volpe et al. PLoS ONE 2012, 7(5), e37208 CCR2 antagonists inhibit chemotaxis and infiltration Vasculature CCL2 release Spinal or Peripheral Tissue Recruited monocyte Site of CCL2 release CCR2 antagonists inhibit chemotaxis and infiltration CCR2 antagonist Circulating monocyte CCL2 release CCL2 release from peripheral injury site or central PAF terminals Role of chemokine system in pathophysiology • Potential role in inflammatory and autoimmune diseases: Multiple sclerosis, Rheumatoid arthritis, COPD, allergic asthma, IBD, psoriasis - Expression levels of chemokines and receptors in relevant tissues and organs of patients and animal disease models - Mouse knockout ppyphenotype in disease models • Established role in HIV infection Katschke et al., 2001 Arthritis Rheum, 44, 1022 - CCR5 and CXCR4 act as HIV-1 co-receptors for virus entry to T-cells (M-tropic and T-topic strains respectively) - Individuals with Δ32-CCR5 mutation protected from HIV infection Garin, Proudfoot Exp. Cell Res. 2011,317, 602-612 Discovery of chemokine receptor antagonists Chemical tractability • Class A GPCRs • Example of protein-protein interaction • Challenging to find low MWt, high LLE antagonists • Small molecule antagonists and agonists • Identified byyg binding/functional assa ys • Allosteric ligands • Early compounds: TAK-779 CCR5/CCR2 Takeda NH2 NH O O BX-471 O F CCR1 N Berlex N Cl Hopkins et al. NRDD 2014,13, 105–121 CCR5 allosteric ligand binding site hypotheses • Receptor homology modelling based on rhodopsin structures • Site directed mutagenesis to identify critical residues • Two hydrophobic pockets - extracellular face of TMI-III & TMIII -VII • Glu283 essential for almost all compound interactions (except TAK-779) • Partially overlaps with endogenous ligand binding site 2 Metz, M. et al. J. Am. Chem. Soc. 2011, 133, 16477-16485 Identification of intracellular allosteric site • Potency measured by inhibiting calcium response • 100 times more potent at CXCR2 than at CXCR1 • Potency increases with increased lipophilicity in cellular Ca2+ flux relative to cell-free radioligand displacement • CXCR1-2-1 chimera constructs used to probe site • Site directed mutagenesis studies • Receptor modelling based on rhodopsin structure • Key amino acid residues influencing antagonism between 302 and 327 (C-terminal tail), particularly 320 (Asp in CXCR1, Lys in CXCR2) Nicholls et al. Mol. Pharm. 2008, 74, 1193-1202 Clinical development of C(X)CR antagonists Receptor Phase 1 Phase 2 Phase 3 Indications CCR1 AVE-1701 BX-471 AZD-4818 MS, psoriasis, endometriosis, RA, BI-638683 MLN-3897 CCX-354 COPD, multiple myeloma CP-481,715 C-6448 CCR2 INCB-8696 MLN-1202a INCB-003284 RA, atherosclerosis, MS, lupus, CCX-915 CCX-140 BMS-741672 type II diabetes, diabetic CCX-872 PF-4136309 MK-0812 neuropathy, pain, allergic rhinitis, JNJ-17166864 PF-04634817 bone metastases AZD-2423 CCR3 DPC-168 ASM-8b GW-766994 asthma, allergic rhinitis MS-639623 AZD-3778 QAP-642 CCR4 GSK-2239633 asthma CCR5 NIBR-6465 UK-127,857 vicriviroc aplaviroc RA, HIV HGS-004a INCB-9471 cenicriviroc TBR-220 PF-232798 PRO-140a SCH-532706 DAPTAd AZD-5672 SB-728c CCR9 CCX-507 vercirnon IBD, Crohn’s CXCR1/2 AZD-4721 navarixin ladarixin reparixin COPD, pancreatic islet transplantation, bullous pemphigoid CXCR2 SB-332235 elubrixin AZD-5069 COPD, cystic fibrosis danirixin PS-291822 CXCR3 AMG-487 T-487 psoriasis CXCR4 MDX-1338a burixafor ALX40-4Cd stem cell transplant, multiple CTCE-9908d POL-6326 AR-177b myeloma, non -Hodgkins AMD-070 BKT-140d olaptesedb lymphona, HIV aNeutralizing monoclonal antibodies. bAntisense oligonucletide. cZinc finger nuclease. dPeptide J. Med. Chem. 2012, 55, 9363. Under Active Development (TR Integrity) Approved C(X)CR antagonists Anti-CCR4 humanised monoclonal antibody Drug Plerixafor Maraviroc Mogamulizumab Brand name Mozobil Celsentri / Selzentry Poteligeo Code name AMD-3100 UK-427857 KW-0761 Originator AnorMED Pfizer Kyowa Hakko Kirin Approved 2003 2007 2012 Receptor CXCR4 CCR5 CCR4 Indications to enhance mobilization of combination antiretroviral relappysed or refractory hematopoietic stem cells for treatment of adults in CCR4-positive adult T- autologous transplantation whom CCR5-tropic HIV-1 cell leukaemia- in patients with lymphoma virus is detectable lymphoma and multippyle myeloma Advanced clinical C(X)CR antagonists Na + O O S O N– N+ Not disclosed – O Cl Drug Vercirnon Reparixin - - Brand name Traficet-EN - - - Code name CCX-282 DF-1681 PF-04634817 CCX354-C Originator ChemoCentryx Dompé Pfizer/Incyte ChemoCentryx Receptor CCR9 CXCR1 CCR2 CCR1 Status Phase 3 for IBD and Phase 3 for prevention Phase 2 for the Evidence of clinical Crohn’s disease of graft dysfunction treatment of type 2 efficacy in RA in a Rights returned by GSK after islet diabetes and overt Phase 2 trial* in 2013 tlttiittransplantation in type nephthhropathy, and Rig hts re turne d by 1 diabetes patients diabetic macular GSK in 2013 edoema *Tak et al. Ann. Rheum. Dis. 2013, 72, 337-344 Chemokine receptor projects at AstraZeneca Overview • Identified small molecule antagonist candidate drugs for almost all chemokine receptor targets prosecuted - CCR1, CCR2, CCR3, CCR4, CCR5, CX3CR1, CXCR2 • Reasons for candidate drug failure (from the 5 ‘R’s publication*): 100% Example: AZD3778 90% • failed to show efficacy in PoP (Phase 2) 80% study in asthma patients 70% • dose limited by safety concerns 60% Strategy • high protein binding and short half-life 50% PK/PD • unclear whether adequate receptor 40% Efficacy exposure had been achieved Safety 30% 20% 10% 0% Preclinical (9) Phase 1 (4) Phase 2 (3) *Projects active 2005-2010 Cook et al. NRDD 2014,13, 419-431 Chemokine receptor projects at AstraZeneca CCR5 antagonists for the treatment of RA Hit-to-Lead HTS hit (SPA binding to Lead optimisation CCR5 membranes) Main issues: hERG, PK Improve LLE AZD5672 Failed in pre-clinical safety - insufficient Sub-nanomolar CCR5 antagonist margin to QT prolongation LLE = 8.1 Cumming, J. G.* et al. Bioorg. Med. Chem. Lett. 2012, 22, 1655-1659 Chemokine receptor projects at AstraZeneca Binding kinetics and potency of AZD5672 • Binding Ki 0.16 nM - displacement of [125I]MIP-1α • Binding Kd 0.10 nM - binding of [3H]-AZD5672 • Dissociation t½ at room temperature >8h8 h • Dissociation t½ at 37°C 68 min. • IC50 MIP-1β induced calcium flux 0.16 nM* • IC50 MIP-1β induced chemotaxis 0.63 nM* • Pseudo A2 MIP-1β induced receptor internalisation in human whole blood 0.76 nM (0.05 nM free drug)* Receptor internalisation 120 control 100 1nM *Cannot measure A values in these nse 2 oo 80 2nM assays due to slow off-rate - pseudo 5nM 60 10nM non-competitive behaviour 40 % max resp 20 0 -10 -9 -8 -7 -6 -5 log MIP-1 conc(M) Chemokine receptor projects at AstraZeneca Clinical development of AZD5672 • Target validation - Expression of CCR5 and its ligands significantly increased in RA patient synovial tissue - Some studies link CCR5Δ32 allele to lower incidence of RA - AZD5672 and other CCR5 antagonists show no activity vs rodent CCR5 - no disease model work undertaken at AZ - Significant effects on clinical arthritis score reported with SCH-X in a rhesus monkey collagen-induced arthritis model • Clinical results - AZD5672 well tolerated and showed good PK in Phase 1 - Phase 2b study in 371 RA patients receiving methotrexate - 20, 50, 100, 150 mg qd AZD5672 vs placebo vs etanercept - Increased rate of infection vs placebo - Failed primary endpoint: no significant effect on ACR20 response at week 12 - Ex vivo receptor internalisation assay showed complete inhibition of CCR5 - Negative results also seen with maraviroc and SCH351125 in RA Gerlag et al. Arthritis Rheum. 2010, 62, 3154-3160 Chemokine receptor projects at AstraZeneca CCR2 antagonists for the treatment of RA singleton HTS hit CCR2 binding IC50 =023µM= 0.23 µM AZD6942 CCR2 binding IC50 = 1.7 µM CCR2 binding IC50 = 0.029 µM Chemotaxis IC50 = 2.5 µM Chemotaxis IC50 = 0.06 µM No rodent activity AZD6942 discontinued in Phase 1 • shorter than predicted half-life • poorly tolerated ‘Discovery and Optimisation of Small Molecule CCR2b Antagonists’ Kettle, J. ACS National Meeting 25 August 2004 Chemokine receptor projects at AstraZeneca 2nd Generation CCR2 antagonist project Cl Cl Cl O O O Cl N N Cl N N F N N H H H N N O N O HN HN N N N singleton HTS hit AZD2423 CCR2 binding IC50 = 170 nM CCR2 binding IC50 = 2.6 nM 2+ 2+ CCR2 Ca flux IC50 = 965 nM CCR2 Ca flux IC50 = 1.2 nM hERG IC50 = 1.6 µM hERG IC50 = 90 µM 2+ Rat CCR2 Ca flux IC50 = 607 nM Cl ~70-fold selective over CCR5 F S O F AZ889 F N N N H CCR2 0. 46 nM N O hERG 16 µM HN Rat CCR2 1.3 0.2 nM N Rat tool compound Cumming, J. G. et al. Bioorg. Med. Chem. Lett. 2012, 22, 3895-3899. Chemokine receptor projects at AstraZeneca Selection of disease indication for AZD2423 • Original target disease was RA • Negative
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