Targeting ERK1/2 protein-serine/threonine kinases in human cancers

Hunter, 2000, Signaling--2000 and beyond, Cell, 100, 113, 10.1016/S0092-8674(00)81688-8 Manning, 2002, The protein kinase complement of the human genome, Science, 298, 1912, 10.1126/science.1075762 Alonso, 2004, Protein tyrosine phosphatases in the human genome, Cell, 117, 699, 10.1016/j.cell.2004.05.018 Burgess, 2017, SnapShot: phosphoregulation of mitosis, Cell, 169, 10.1016/j.cell.2017.06.003 Bononi, 2011, Protein kinases and phosphatases in the control of cell fate, Enzyme Res., 10.4061/2011/329098 Schaeffer, 1999, Mitogen-activated protein kinases: specific messages from ubiquitous messengers, Mol. Cell. Biol., 19, 2435, 10.1128/MCB.19.4.2435 Dhillon, 2007, MAP kinase signalling pathways in cancer, Oncogene, 26, 3279, 10.1038/sj.onc.1210421 Cargnello, 2011, Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases, Microbiol. Mol. Biol. Rev., 75, 50, 10.1128/MMBR.00031-10 Plotnikov, 2011, The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation, Biochim. Biophys. Acta, 1813, 1619, 10.1016/j.bbamcr.2010.12.012 Morrison, 2003, Regulation of MAP kinase signaling modules by scaffold proteins in mammals, Annu. Rev. Cell Dev. Biol., 19, 91, 10.1146/annurev.cellbio.19.111401.091942 Whitmarsh, 2006, The JIP family of MAPK scaffold proteins, Biochem. Soc. Trans., 34, 828, 10.1042/BST0340828 Roskoski, 2018, Targeting oncogenic Raf protein-serine/threonine kinases in human cancers, Pharmacol. Res., 135, 239, 10.1016/j.phrs.2018.08.013 Malumbres, 2003, RAS oncogenes: the first 30 years, Nat. Rev. Cancer, 3, 459, 10.1038/nrc1097 Stephen, 2014, Dragging Ras back in the ring, Cancer Cell, 25, 272, 10.1016/j.ccr.2014.02.017 Simanshu, 2017, RAS proteins and their regulators in human disease, Cell, 170, 17, 10.1016/j.cell.2017.06.009 Roskoski, 2010, RAF protein-serine/threonine kinases: structure and regulation, Biochem. Biophys. Res. Commun., 399, 313, 10.1016/j.bbrc.2010.07.092 Roskoski, 2012, MEK1/2 dual-specificity protein kinases: structure and regulation, Biochem. Biophys. Res. Commun., 417, 5, 10.1016/j.bbrc.2011.11.145 Roskoski, 2017, Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas, Pharmacol. Res., 117, 20, 10.1016/j.phrs.2016.12.009 Roskoski, 2012, ERK1/2 MAP kinases: structure, function, and regulation, Pharmacol. Res., 66, 105, 10.1016/j.phrs.2012.04.005 Ünal, 2017, A compendium of ERK targets, FEBS Lett., 591, 2607, 10.1002/1873-3468.12740 Raman, 2007, Differential regulation and properties of MAPKs, Oncogene, 26, 3100, 10.1038/sj.onc.1210392 Weston, 2007, The JNK signal transduction pathway, Curr. Opin. Cell Biol., 19, 142, 10.1016/j.ceb.2007.02.001 Hanks, 1991, Eukaryotic protein kinases, Curr. Opin. Struct. Biol., 1, 369, 10.1016/0959-440X(91)90035-R Lefloch, 2009, Total ERK1/2 activity regulates cell proliferation, Cell Cycle, 8, 705, 10.4161/cc.8.5.7734 Samatar, 2014, Targeting RAS-ERK signalling in cancer: promises and challenges, Nat. Rev. Drug Discov., 13, 928, 10.1038/nrd4281 Faivre, 2006, New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors, Semin. Oncol., 33, 407, 10.1053/j.seminoncol.2006.04.005 Baines, 2011, Inhibition of Ras for cancer treatment: the search continues, Future Med. Chem., 3, 1787, 10.4155/fmc.11.121 Khan, 2018, RAS-mediated oncogenic signaling pathways in human malignancies, Semin. Cancer Biol. Pylayeva-Gupta, 2011, RAS oncogenes: weaving a tumorigenic web, Nat. Rev. Cancer, 11, 761, 10.1038/nrc3106 Ostrem, 2016, Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design, Nat. Rev. Drug Discov., 15, 771, 10.1038/nrd.2016.139 Statsyuk, 2018, Let K-Ras activate its own inhibitor, Nat. Struct. Mol. Biol., 25, 435, 10.1038/s41594-018-0066-0 Hansen, 2018, The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors, Nat. Struct. Mol. Biol., 25, 454, 10.1038/s41594-018-0061-5 Chuang, 2017, Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer, Pharmacol. Res., 117, 370, 10.1016/j.phrs.2017.01.006 O’Bryan, 2018, Pharmacological targeting of RAS: recent success with direct inhibitors, Pharmacol. Res. Hodis, 2012, A landscape of driver mutations in melanoma, Cell, 150, 251, 10.1016/j.cell.2012.06.024 Cancer Genome Atlas Network, 2015, Genomic classification of cutaneous melanoma, Cell, 161, 1681, 10.1016/j.cell.2015.05.044 Namba, 2003, Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers, J. Clin. Endocrinol. Metab., 88, 4393, 10.1210/jc.2003-030305 Jones, 2017, Non-V600BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer, J. Clin. Oncol., 35, 2624, 10.1200/JCO.2016.71.4394 Cardarella, 2013, Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer, Clin. Cancer Res., 19, 4532, 10.1158/1078-0432.CCR-13-0657 Paik, 2011, Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations, J. Clin. Oncol., 29, 2046, 10.1200/JCO.2010.33.1280 Yuen, 2002, Mutations of the BRAF gene in human cancer, Nature, 417, 949, 10.1038/nature00766 Fischer, 2017, Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview, Med. Res. Rev., 37, 314, 10.1002/med.21409 Eisen, 2006, Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis, Br. J. Cancer, 95, 581, 10.1038/sj.bjc.6603291 Chapman, 2011, Improved survival with vemurafenib in melanoma with BRAF V600E mutation, N. Engl. J. Med., 364, 2507, 10.1056/NEJMoa1103782 Zhao, 2014, The clinical development of MEK inhibitors, Nat. Rev. Clin. Oncol., 11, 385, 10.1038/nrclinonc.2014.83 Hauschild, 2012, Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial, Lancet, 380, 358, 10.1016/S0140-6736(12)60868-X Flaherty, 2012, Improved survival with MEK inhibition in BRAF-mutated melanoma, N. Engl. J. Med., 367, 107, 10.1056/NEJMoa1203421 Kim, 2013, Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor, J. Clin. Oncol., 31, 482, 10.1200/JCO.2012.43.5966 Flaherty, 2012, Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations, N. Engl. J. Med., 367, 1694, 10.1056/NEJMoa1210093 Larkin, 2014, Combined vemurafenib and cobimetinib in BRAF-mutated melanoma, N. Engl. J. Med., 371, 1867, 10.1056/NEJMoa1408868 Dummer, 2018, Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial, Lancet Oncol., 19, 603, 10.1016/S1470-2045(18)30142-6 Smalley, 2016, Combination therapies for melanoma: a new standard of care?, Am. J. Clin. Dermatol., 17, 99, 10.1007/s40257-016-0174-8 Sharma, 2015, The future of immune checkpoint therapy, Science, 348, 56, 10.1126/science.aaa8172 Luke, 2017, Targeted agents and immunotherapies: optimizing outcomes in melanoma, Nat. Rev. Clin. Oncol., 14, 463, 10.1038/nrclinonc.2017.43 Kuske, 2018, Immunomodulatory effects of BRAF and MEK inhibitors: implications for melanoma therapy, Pharmacol. Res., 136, 151, 10.1016/j.phrs.2018.08.019 Ramello, 2018, CAR-T cells and combination therapies: What’s next in the immunotherapy revolution?, Pharmacol. Res., 129, 194, 10.1016/j.phrs.2017.11.035 Kidger, 2018, ERK1/2 inhibitors: new weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway, Pharmacol. Ther., 187, 45, 10.1016/j.pharmthera.2018.02.007 Knighton, 1991, Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase, Science, 253, 407, 10.1126/science.1862342 Knighton, 1991, Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase, Science, 253, 414, 10.1126/science.1862343 Taylor, 2011, Protein kinases: evolution of dynamic regulatory proteins, Trends Biochem. Sci., 36, 65, 10.1016/j.tibs.2010.09.006 Kornev, 2015, Dynamics-driven allostery in protein kinases, Trends Biochem. Sci., 40, 628, 10.1016/j.tibs.2015.09.002 Vijayan, 2015, Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors, J. Med. Chem., 58, 466, 10.1021/jm501603h Kooistra, 2017, Kinase-centric computational drug development, Ann. Rep. Med. Chem., 50, 197 Roskoski, 2019, Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs, Pharmacol. Res., 139, 471, 10.1016/j.phrs.2018.11.035 Zhang, 1994, Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution, Nature, 367, 704, 10.1038/367704a0 Hanks, 1995, Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification, FASEB J., 9, 576, 10.1096/fasebj.9.8.7768349 Gibbs, 1991, Rational scanning mutagenesis of a protein kinase identifies functional regions involved in catalysis and substrate interactions, J. Biol. Chem., 266, 8923, 10.1016/S0021-9258(18)31532-1 Madhusudan, 1994, cAMP-dependent protein kinase: crystallographic insights into substrate recognition and phosphotransfer, Protein Sci., 3, 176, 10.1002/pro.5560030203 Zhou, 1997, Participation of ADP dissociation in the rate-determining step in cAMP-dependent protein kinase, Biochemistry, 36, 15733, 10.1021/bi971438n Schwartz, 2011, Protein kinase biochemistry and drug discovery, Bioorg. Chem., 39, 192, 10.1016/j.bioorg.2011.07.004 Kornev, 2010, Defining the conserved internal architecture of a protein kinase, Biochim. Biophys. Acta, 1804, 440, 10.1016/j.bbapap.2009.10.017 Waas, 2003, Physiological concentrations of divalent magnesium ion activate the serine/threonine specific protein kinase ERK2, Biochemistry, 42, 2960, 10.1021/bi027171w Canagarajah, 1997, Activation mechanism of the MAP kinase ERK2 by dual phosphorylation, Cell, 90, 859, 10.1016/S0092-8674(00)80351-7 Davis, 1993, The mitogen-activated protein kinase signal transduction pathway, J. Biol. Chem., 268, 14553, 10.1016/S0021-9258(18)82362-6 Johnson, 2001, Dynamics of cAMP-dependent protein kinase, Chem. Rev., 101, 2243, 10.1021/cr000226k Kemp, 1977, Role of multiple basic residues in determining the substrate specificity of cyclic AMP-dependent protein kinase, J. Biol. Chem., 252, 4888, 10.1016/S0021-9258(17)40137-2 Pearson, 2001, Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions, Endocr. Rev., 22, 153 Jacobs, 1999, Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase, Genes Dev., 13, 163, 10.1101/gad.13.2.163 Bermudez, 2010, The dual-specificity MAP kinase phosphatases: critical roles in development and cancer, Am. J. Physiol., Cell Physiol., 299, C189, 10.1152/ajpcell.00347.2009 Hari, 2013, Sequence determinants of a specific inactive protein kinase conformation, Chem. Biol., 20, 806, 10.1016/j.chembiol.2013.05.005 Roskoski, 2015, A historical overview of protein kinases and their targeted small molecule inhibitors, Pharmacol. Res., 100, 1, 10.1016/j.phrs.2015.07.010 Kornev, 2006, Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism, Proc. Natl. Acad. Sci. U. S. A., 103, 17783, 10.1073/pnas.0607656103 Kornev, 2008, A helix scaffold for the assembly of active protein kinases, Proc. Natl. Acad. Sci. U. S. A., 105, 14377, 10.1073/pnas.0807988105 Meharena, 2013, Deciphering the structural basis of eukaryotic protein kinase regulation, PLoS Biol., 11, 10.1371/journal.pbio.1001680 Roskoski, 2016, Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes, Pharmacol. Res., 103, 26, 10.1016/j.phrs.2015.10.021 Roskoski, 2013, Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition, Pharmacol. Res., 68, 68, 10.1016/j.phrs.2012.11.007 Roskoski, 2017, Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers, Pharmacol. Res., 117, 343, 10.1016/j.phrs.2017.01.007 Roskoski, 2016, Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs, Pharmacol. Res., 111, 784, 10.1016/j.phrs.2016.07.038 Roskoski, 2019, Cyclin-dependent protein serine/threonine inhibitors as anticancer drugs, Pharmacol. Res., 139, 471, 10.1016/j.phrs.2018.11.035 Roskoski, 2014, The ErbB/HER family of protein-tyrosine kinases and cancer, Pharmacol. Res., 79, 34, 10.1016/j.phrs.2013.11.002 Roskoski, 2014, ErbB/HER protein-tyrosine kinases: structures and small molecule inhibitors, Pharmacol. Res., 87, 42, 10.1016/j.phrs.2014.06.001 Roskoski, 2019, Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers, Pharmacol. Res., 139, 395, 10.1016/j.phrs.2018.11.014 Roskoski, 2016, Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases, Pharmacol. Res., 111, 784, 10.1016/j.phrs.2016.07.038 Roskoski, 2018, The role of small molecule Kit protein-tyrosine kinase inhibitors in the treatment of neoplastic disorders, Pharmacol. Res., 133, 35, 10.1016/j.phrs.2018.04.020 Roskoski, 2018, The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders, Pharmacol. Res., 129, 65, 10.1016/j.phrs.2018.01.021 Roskoski, 2018, Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers, Pharmacol. Res., 128, 1, 10.1016/j.phrs.2017.12.021 Roskoski, 2017, ROS1 protein-tyrosine kinase inhibitors in the treatment of ROS1 fusion protein-driven non-small cell lung cancers, Pharmacol. Res., 121, 202, 10.1016/j.phrs.2017.04.022 Roskoski, 2015, Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors, Pharmacol. Res., 94, 9, 10.1016/j.phrs.2015.01.003 Frame, 2017, Src family tyrosine kinases, 1 Roskoski, 2017, Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas, Pharmacol. Res., 120, 116, 10.1016/j.phrs.2017.03.010 Kim, 2017, A dynamic hydrophobic core orchestrates allostery in protein kinases, Sci. Adv., 3, 10.1126/sciadv.1600663 Liu, 1998, A molecular gate which controls unnatural ATP analogue recognition by the tyrosine kinase v-Src, Bioorg. Med. Chem., 6, 1219, 10.1016/S0968-0896(98)00099-6 Dar, 2011, The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling, Annu. Rev. Biochem., 80, 769, 10.1146/annurev-biochem-090308-173656 Vulpetti, 2004, Sequence and structural analysis of kinase ATP pocket residues, Farmaco, 59, 759, 10.1016/j.farmac.2004.05.010 Haystead, 1992, Ordered phosphorylation of p42mapk by MAP kinase kinase, FEBS Lett., 306, 17, 10.1016/0014-5793(92)80828-5 Burack, 1997, The activating dual phosphorylation of MAPK by MEK is nonprocessive, Biochemistry, 36, 5929, 10.1021/bi970535d Ferrell, 1997, Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase, J. Biol. Chem., 272, 19008, 10.1074/jbc.272.30.19008 Anderson, 1990, Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase, Nature, 343, 651, 10.1038/343651a0 Hermiston, 2009, CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells, Immunol. Rev., 228, 288, 10.1111/j.1600-065X.2008.00752.x Eichhorn, 2009, Protein phosphatase 2A regulatory subunits and cancer, Biochim. Biophys. Acta, 1795, 1 Ruvolo, 2019, Role of protein phosphatases in the cancer microenvironment, Biochim. Biophys. Acta Mol. Cell Res., 1866, 144, 10.1016/j.bbamcr.2018.07.006 Taylor, 2012, Evolution of the eukaryotic protein kinases as dynamic molecular switches, Philos. Trans. R. Soc. Lond. Biol. Sci., 367, 2517, 10.1098/rstb.2012.0054 Zuccotto, 2010, Through the "gatekeeper door": exploiting the active kinase conformation, J. Med. Chem., 53, 2691, 10.1021/jm901443h Gavrin, 2013, Approaches to discover non-ATP site inhibitors, Med. Chem. Res., 4, 41 Lamba, 2012, New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors, Curr. Pharm. Des., 18, 2936, 10.2174/138161212800672813 Johnson, 2016, Bivalent inhibitors of c-Src tyrosine kinase that bind a regulatory domain, Bioconjug. Chem., 27, 1745, 10.1021/acs.bioconjchem.6b00243 Kwarcinski, 2016, Conformation-selective analogues of dasatinib reveal insight into kinase inhibitor binding and selectivity, ACS Chem. Biol., 11, 1296, 10.1021/acschembio.5b01018 Zhao, 2014, Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery?, ACS Chem. Biol., 9, 1230, 10.1021/cb500129t Copeland, 2016, The drug-target residence time model: a 10-year retrospective, Nat. Rev. Drug Discov., 15, 87, 10.1038/nrd.2015.18 Ung, 2018, Redefining the protein kinase conformational space with machine learning, Cell Chem. Biol., 25, 10.1016/j.chembiol.2018.05.002 Liao, 2007, Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors, J. Med. Chem., 50, 409, 10.1021/jm0608107 van Linden, 2014, KLIFS: a knowledge-based structural database to navigate kinase-ligand interaction space, J. Med. Chem., 57, 249, 10.1021/jm400378w Bajusz, 2017, Structure-based virtual screening approaches in kinase-directed drug discovery, Curr. Top. Med. Chem., 17, 2235, 10.2174/1568026617666170224121313 Fabbro, 2015, Ten things you should know about protein kinases: IUPHAR Review 14, Br. J. Pharmacol., 172, 2675, 10.1111/bph.13096 Cavallo, 2016, The halogen bond, Chem. Rev., 116, 2478, 10.1021/acs.chemrev.5b00484 Carles, 2018, PKIDB: a curated, annotated and updated database of protein kinase inhibitors in clinical trials, Molecules, 23, 10.3390/molecules23040908 Germann, 2017, Targeting the MAPK signaling pathway in cancer: promising preclinical activity with the novel selective ERK1/2 inhibitor BVD-523 (ulixertinib), Mol. Cancer Ther., 16, 2351, 10.1158/1535-7163.MCT-17-0456 Sullivan, 2018, First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study, Cancer Discov., 8, 184, 10.1158/2159-8290.CD-17-1119 Boga, 2018, MK-8353: discovery of an orally bioavailable dual mechanism ERK inhibitor for oncology, ACS Med. Chem. Lett., 9, 761, 10.1021/acsmedchemlett.8b00220 Moschos, 2018, Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors, JCI Insight, 3, 10.1172/jci.insight.92352 Blake, 2016, Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor in early clinical development, J. Med. Chem., 59, 5650, 10.1021/acs.jmedchem.6b00389 Morris, 2013, Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors, Cancer Discov., 3, 742, 10.1158/2159-8290.CD-13-0070 Heightman, 2018, Fragment-based discovery of a potent, orally bioavailable inhibitor that modulates the phosphorylation and catalytic activity of ERK1/2, J. Med. Chem., 61, 4978, 10.1021/acs.jmedchem.8b00421 Wang, 2018, AGO1 may influence the prognosis of hepatocellular carcinoma through TGF-β pathway, Cell Death Dis., 9, 324, 10.1038/s41419-018-0338-y Aronchik, 2018, Efficacy of a covalent ERK1/2 inhibitor, CC-90003, in KRAS mutant cancer models reveals novel mechanisms of response and resistance, Mol. Cancer Res. Liu, 2018, Targeting ERK, an Achilles’ heel of the MAPK pathway, in cancer therapy, Acta Pharm. Sin. B, 8, 552, 10.1016/j.apsb.2018.01.008 Jaiswal, 2018, ERK mutations and amplification confer resistance to ERK-inhibitor therapy, Clin. Cancer Res., 24, 4044, 10.1158/1078-0432.CCR-17-3674 Lipinski, 1997, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev., 23, 3, 10.1016/S0169-409X(96)00423-1 Hopkins, 2004, Ligand efficiency: a useful metric for lead selection, Drug Discov. Today, 9, 430, 10.1016/S1359-6446(04)03069-7 Smith, 2009, Medicinal chemistry by the numbers: the physicochemistry, thermodynamics and kinetics of modern drug design, Prog. Med. Chem., 48, 1, 10.1016/S0079-6468(09)04801-2 Leeson, 2007, The influence of drug-like concepts on decision-making in medicinal chemistry, Nat. Rev. Drug Discov., 6, 881, 10.1038/nrd2445 Lipinski, 2016, Rule of five in 2015 and beyond: target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions, Adv. Drug Deliv. Rev., 101, 34, 10.1016/j.addr.2016.04.029 Ekins, 2016, Thermodynamic proxies to compensate for biases in drug discovery methods, Pharm. Res., 33, 194, 10.1007/s11095-015-1779-y Hopkins, 2014, The role of ligand efficiency metrics in drug discovery, Nat. Rev. Drug Discov., 13, 105, 10.1038/nrd4163 Leeson, 2016, Molecular inflation, attrition, and the rule of five, Adv. Drug Deliv. Rev., 101, 22, 10.1016/j.addr.2016.01.018 Cavalluzzi, 2017, Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective, Expert Opin. Drug Discov., 12, 1087, 10.1080/17460441.2017.1365056 Myers, 2016, AXL inhibitors in cancer: a medicinal chemistry perspective, J. Med. Chem., 59, 3593, 10.1021/acs.jmedchem.5b01273 Roth, 2004, Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia, Nat. Rev. Drug Discov., 3, 353, 10.1038/nrd1346 Kaufman, 2018, Glaucoma drugs in the pipeline, Asia Pac. J. Ophthalmol. (Phila.), 7, 345 Cohen, 2013, Kinase drug discovery--what’s next in the field?, ACS Chem. Biol., 8, 96, 10.1021/cb300610s Budzyn, 2006, Targeting Rho and Rho-kinase in the treatment of cardiovascular disease, Trends Pharmacol. Sci., 27, 97, 10.1016/j.tips.2005.12.002 Goldstein, 2010, Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders, J. Med. Chem., 53, 2345, 10.1021/jm9012906 Mok, 2019, The jakinibs in systemic lupus erythematosus: progress and prospects, Expert Opin. Investig. Drugs, 28, 85, 10.1080/13543784.2019.1551358 Schenck Eidam, 2018, Discovery of a first-in-class gut-restricted RET kinase inhibitor as a clinical candidate for the treatment of IBS, ACS Med. Chem. Lett., 9, 623, 10.1021/acsmedchemlett.8b00035 Wan, 2017, Evaluation and characterization of Trk kinase inhibitors for the treatment of pain: reliable binding affinity predictions from theory and computation, J. Chem. Inf. Model., 57, 897, 10.1021/acs.jcim.6b00780 Golpich, 2015, Glycogen synthase kinase-3 beta (GSK-3β) signaling: implications for Parkinson’s disease, Pharmacol. Res., 97, 16, 10.1016/j.phrs.2015.03.010 Nozal, 2019, Tau Tubulin Kinase 1 (TTBK1), a new player in the fight against neurodegenerative diseases, Eur. J. Med. Chem., 161, 39, 10.1016/j.ejmech.2018.10.030 Nygaard, 2015, A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease, Alzheimers Res. Ther., 7, 35, 10.1186/s13195-015-0119-0 Siu, 2018, Dual leucine zipper kinase inhibitors for the treatment of neurodegeneration, J. Med. Chem., 61, 8078, 10.1021/acs.jmedchem.8b00370 Palomo, 2017, Subtly modulating glycogen synthase kinase 3 β: allosteric inhibitor development and their potential for the treatment of chronic diseases, J. Med. Chem., 60, 4983, 10.1021/acs.jmedchem.7b00395 Ferguson, 2018, Kinase inhibitors: the road ahead, Nat. Rev. Drug Discov., 17, 353, 10.1038/nrd.2018.21 Joussen, 2018, The Developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial, Br. J. Clin. Pharmacol. Nussinov, 2019, Precision medicine review: rare driver mutations and their biophysical classification, Biophys. Rev., 10.1007/s12551-018-0496-2 Williams-Ashman, 1952, Oxidative phosphorylation catalyzed by cytoplasmic particles isolated from malignant tissues, Cancer Res., 12, 415 Kennedy, 1954, The isolation of radioactive phosphoserine from phosphoprotein of the Ehrlich ascites tumor, J. Biol. Chem., 207, 153, 10.1016/S0021-9258(18)71254-4 Burnett, 1954, The enzymatic phosphorylation of proteins, J. Biol. Chem., 211, 969, 10.1016/S0021-9258(18)71184-8 Tao, 2015, Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs, Pharmacol. Res., 102, 123, 10.1016/j.phrs.2015.09.019 Roskoski, 2017, Guidelines for preparing color figures for everyone including the colorblind, Pharmacol. Res., 119, 240, 10.1016/j.phrs.2017.02.005