Discoidin domain receptor inhibitors as anticancer agents: A systematic review on recent development of DDRs inhibitors, their resistance and structure activity relationship

Nagai, 2017, Cancer prevention from the perspective of global cancer burden patterns, J. Thorac. Dis., 9, 448, 10.21037/jtd.2017.02.75 Fearon, 2006, Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis, Am. J. Clin. Nutr., 83, 1345, 10.1093/ajcn/83.6.1345 Mehlen, 2006, Metastasis: a question of life or death, Nat. Rev. Cancer, 6, 449, 10.1038/nrc1886 Cancer [Internet]. [cited 2022 Aug 18]. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer. Zeromski, 2002, Significance of tumor-cell receptors in human cancer, Arch. Immunol. Ther. Exp. (Warsz), 50, 105 Metibemu, 2019, Exploring receptor tyrosine kinases-inhibitors in Cancer treatments, Egyptian J. Med. Human Genet., 20, 35, 10.1186/s43042-019-0035-0 Röhm, 2021, Development of a selective dual discoidin domain receptor (DDR)/p38 kinase chemical probe, J. Med. Chem., 64, 13451, 10.1021/acs.jmedchem.1c00868 Gao, 2021, Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies, Cancer Sci., 112, 962, 10.1111/cas.14789 Lemmon, 2010, Cell signaling by receptor tyrosine kinases, Cell, 141, 1117, 10.1016/j.cell.2010.06.011 Vogel, 2001, Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development, Mol. Cell. Biol., 21, 2906, 10.1128/MCB.21.8.2906-2917.2001 Hou, 2001, The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair, J. Clin. Investig., 107, 727, 10.1172/JCI10720 Najafi, 2019, Extracellular matrix (ECM) stiffness and degradation as cancer drivers, J. Cell. Biochem., 120, 2782, 10.1002/jcb.27681 H. Xu, D. Bihan, F. Chang, P.H. Huang, R.W. Farndale, B. Leitinger, Discoidin Domain Receptors Promote α1β1- and α2β1-Integrin Mediated Cell Adhesion to Collagen by Enhancing Integrin Activation, PLoS One. 7(12) (2012 Dec 20) e52209. Lu, 2012, The extracellular matrix: A dynamic niche in cancer progression, J. Cell Biol., 196, 395, 10.1083/jcb.201102147 Herrera-Herrera, 2012, DDR2 plays a role in fibroblast migration independent of adhesion ligand and collagen activated DDR2 tyrosine kinase, Biochem. Biophys. Res. Commun., 429, 39, 10.1016/j.bbrc.2012.10.103 Faraci-Orf, 2006, DDR1 signaling is essential to sustain Stat5 function during lactogenesis, J. Cell. Biochem., 97, 109, 10.1002/jcb.20618 B. Leitinger, Discoidin domain receptor functions in physiological and pathological conditions. In 2014. p. 39–87. Hebron, 2017, Discoidin domain receptor inhibition reduces neuropathology and attenuates inflammation in neurodegeneration models, J. Neuroimmunol., 311, 1, 10.1016/j.jneuroim.2017.07.009 Borza, 2014, Discoidin domain receptors in disease, Matrix Biol., 34, 185, 10.1016/j.matbio.2013.12.002 S. Moll, A. Desmoulière, M.J. Moeller, J.C. Pache, L. Badi, F. Arcadu, et al., DDR1 role in fibrosis and its pharmacological targeting. Biochim. Biophys. Acta (BBA) – Mol. Cell Res. 2019 Nov;1866(11):118474. Dorison, 2017, The role of discoidin domain receptor 1 in inflammation, fibrosis and renal disease, Nephron., 137, 212, 10.1159/000479119 Rix, 2007, Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets, Blood, 110, 4055, 10.1182/blood-2007-07-102061 Victoria Smith, Scott Alan Mccauley, Maria Vaysberg, Joanne I. Adamkewicz, WO2014047624A1 - Anti-ddr1 antibodies - Google Patents [Internet]. 2014 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/WO2014047624A1/en. Peter Sennhenn, Sebastian Meier-Ewert, Nisit Khandelwal. US20210379067A1 - Dasatinib and another 5-thiazolecarboxamide kinase inhibitor, and uses thereof - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/US20210379067A1/en?oq=US20210379067A1. Li Runsheng. WO2019219089A1 - Anti-claudin 18.2 antibodies and uses thereof - Google Patents [Internet]. 2019 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/WO2019219089A1/en?oq=WO2019219089A1. Zavoronkovs Aleksandrs, IvanenkovYan, Polykovskiy Daniil, Aliper Aleksandr. WO2021038419A1 - Kinase inhibitors and methods of synthesis and treatment - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/WO2021038419A1/en?oq=WO2021038419A1. H. Chu, J.A. Guerrero, A.E. Hurtley, T.H. Hwang, TWI719478B - Mcl-1 inhibitors - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/TWI719478B/en?oq=TWI719478B. B. Xiong, J. Li, M. Geng, J. Shen Ai, J. Zang Yi TW202116740A - Compound of fused aminopyrimidine, and preparaing method, pharmaceutical composition and application thereof - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/TW202116740A/en?oq=TW202116740A. L. Fang, Y. Wang, Z. Wang, B. Guo, J. Zang, BR112020019827A2 - Antibody or fragment of the same, biespecific antibody, composition, nucleotide polynucleotide, isolated cell, and, methods for treating cancer or infection and detecting the expression of pd-l1 in a sample - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/BR112020019827A2/en?oq=BR112020019827A2. S. Peter, S. Meier-Ewert, N. Khandelwal, WO2020083909A1 - Dasatinib and another 5-thiazolecarboxamide kinase inhibitor, and uses thereof - Google Patents [Internet]. 2020 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/WO2020083909A1/en?oq=WO2020083909A1. G. Bircus, M. Dejmek, R. Nencka, O. Pav, M. Sala, TW202014193A - 2’3’-cyclic dinucleotides comprising carbocyclic nucleotide - Google Patents [Internet]. 2020 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/TW202014193A/en?oq=TW202014193A. L. Carzaniga, F. Rancati, A. Rizzi, Anna Karawajczyk, B.P. Gut, WO2021239643A1 - Benzylamine derivatives as ddrs inhibitors - Google Patents [Internet]. 2021 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/WO2021239643A1/en?oq=WO2021239643A1. C.C. Stinson, O.R. Barbeau, M.R. Pizzoonero, R.P. Modric, T.T. Thang Mai, A.M. Joncour, et al., TW202216678A - Novel compounds and pharmaceutical compositions thereof for the treatment of diseases - Google Patents [Internet]. 2022 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/TW202216678A/en?oq=TW202216678A. Vandroux D, Prost E, Souilles L. FR3112942A1 - Immunomodulatory protein ligands derived from collagen usable by injection - Google Patents [Internet]. 2022 [cited 2022 Aug 18]. Available from: https://patents.google.com/patent/FR3112942A1/en?oq=FR3112942A1. Brekken RA, Ding K, Ren X, Tu Z, Wang Z, Aguilera KY. US10370360B2 - Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof - Google Patents [Internet]. 2018 [cited 2022 Oct 7]. p. 1–88. Available from: https://patents.google.com/patent/US10370360B2/en?q=DDR1%2c+DDR2+small+molecules&oq=DDR1%2c+DDR2+small+molecules. Dasatinib in advanced squamous cell lung cancer - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT01491633. Testing dasatinib as a potential targeted treatment in cancers with DDR2 genetic changes (MATCH-Subprotocol X) - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT04439305. Trial of dasatinib in patients with advanced cancers harboring DDR2 mutation or inactivating B-RAF mutation - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01514864. Bauer T, Cho BC, Heist R, Bazhenova L, Werner T, Goel S, et al. First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors. Invest New Drugs [Internet]. 2022 Jun 29 [cited 2022 Aug 18]; Available from: https://clinicaltrials.gov/ct2/show/NCT02219711. Impact of ctDNA in cancer early detection and STAS evaluation in patients with GGOs - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT05187767. NSCLC heterogeneity in early stage patients and prediction of relapse using a personalized “Liquid Biopsy” - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03771404. Targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma (The MATCH Screening Trial) - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT02465060. Adapting treatment to the tumor molecular alterations for patients with advanced solid tumors: MyOwnSpecificTreatment - Full Text View - ClinicalTrials.gov [Internet]. [cited 2022 Aug 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT02029001. Kiedzierska, 2007, Structural similarities and functional diversity of eukaryotic discoidin-like domains, Biochim. Biophys. Acta (BBA) - Proteins Proteomics., 1774, 10.1016/j.bbapap.2007.07.007 Shrivastava, 1997, An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors, Mol. Cell, 1, 10.1016/S1097-2765(00)80004-0 Vogel, 1997, The discoidin domain receptor tyrosine kinases are activated by collagen, Mol. Cell, 1, 10.1016/S1097-2765(00)80003-9 Valiathan, 2012, Discoidin domain receptor tyrosine kinases: new players in cancer progression, Cancer Metastasis Rev., 31 Matada, 2021, DDR1 and DDR2: A review on signaling pathway and small molecule inhibitors as an anticancer agent, Vol. 30, 535 Fu, 2013, Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling, J. Biol. Chem., 288, 7430, 10.1074/jbc.R112.444158 Alves, 2001, Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines, FASEB J., 15, 1321, 10.1096/fj.00-0626fje Jin, 2008, Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis, Arthritis Res Ther., 10, R73, 10.1186/ar2447 Kiedzierska, 2007, Structural similarities and functional diversity of eukaryotic discoidin-like domains. Biochimica et Biophysica Acta (BBA) -, Proteins and Proteomics., 1774, 1069, 10.1016/j.bbapap.2007.07.007 Curat, 2001, Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding, J. Biol. Chem., 276, 45952, 10.1074/jbc.M104360200 Leitinger, 2003, Molecular analysis of collagen binding by the human discoidin domain, DDR1 and DDR2, J. Biol. Chem., 278, 10.1074/jbc.M301370200 Xu, 2011, Collagen binding specificity of the discoidin domain receptors: Binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1, Matrix Biol., 30, 16, 10.1016/j.matbio.2010.10.004 I. Berestjuk, M. Lecacheur, A. Carminati, S. Diazzi, C. Rovera, V. Prod’homme, et al., Targeting discoidin domain receptors DDR1 and DDR2 overcomes matrix‐mediated tumor cell adaptation and tolerance to BRAF‐targeted therapy in melanoma. EMBO Mol Med. 2022 Feb 7;14(2). Ford, 2007, Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma, Br. J. Cancer, 96, 5, 10.1038/sj.bjc.6603614 J.D. Johnson, J.C. Edmant, W.J. Rutter, A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Vol. 90, Proc. Natl. Acad. Sci. USA. 1993. Moon. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncol Rep. 2010 Jun 25;24(2). S.K. Hanks, A.M. Quinn, T. Hunter, The protein kinase family: Conserved features and deduced phylogeny of the catalytic. Vol. 241, Source: Science, New Series. 1988. Karn, 1993, Structure, expression and chromosomal mapping of TKT from man and mouse: a new subdass of receptor tyrosine kinases with a factor VIII-like domain, Oncogene, Vol. 8 Alves, 1995, Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer, Oncogene, 10, 3 Alves, 2001, Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines, FASEB J., 15, 1321, 10.1096/fj.00-0626fje Wang, 2005, Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel, J. Cell. Physiol., 203, 295, 10.1002/jcp.20227 Vella, 2019, Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection. Biochimica et Biophysica Acta (BBA) - Molecular, Cell Res., 1866 Malaguarnera, 2015, Novel cross-talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses, Oncotarget., 6, 16084, 10.18632/oncotarget.3177 Abdulhussein, 2004, Exploring the collagen-binding site of the DDR1 tyrosine kinase receptor, J. Biol. Chem., 279, 31462, 10.1074/jbc.M400651200 Leitinger, 2003, Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2, J. Biol. Chem., 278, 10.1074/jbc.M301370200 Leitinger, 2004, The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2, J. Mol. Biol., 344, 10.1016/j.jmb.2004.09.089 Leitinger, 2006, The discoidin domain receptor DDR2 is a receptor for type X collagen, Matrix Biol., 25, 10.1016/j.matbio.2006.05.006 Miao, 2013, Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition, Med. Oncol., 30, 626, 10.1007/s12032-013-0626-4 Leitinger, 2011, Transmembrane collagen receptors, Annu. Rev. Cell Dev. Biol., 27, 265, 10.1146/annurev-cellbio-092910-154013 Shintani, 2008, Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor, J. Cell Biol., 180, 1277, 10.1083/jcb.200708137 Lin, 2010, Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation, J. Bone Miner. Res., 25, 2489, 10.1002/jbmr.159 Carafoli, 2013, Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochimica et Biophysica Acta (BBA) -, Proteins and Proteomics., 1834, 2187, 10.1016/j.bbapap.2012.10.014 Yeh, 2011, DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin, Mol. Biol. Cell, 22, 940, 10.1091/mbc.e10-08-0678 Dorison, 2018, DDR1: A major player in renal diseases, Cell Adh Migr., 27, 1, 10.1080/19336918.2018.1441661 A. Zhu, Y. Liu, X. Lin, Roles of discoidin domain receptor 1 in gastrointestinal tumors, Dig Med Res. 2019 Jul;2:13–13. Sánchez, 1994, Multiple tyrosine protein kinases in rat hippocampalneurons: isolation of Ptk-3, a receptor expressed in proliferative zones of thedeveloping brain, Proc. Natl. Acad. Sci., 91, 1819, 10.1073/pnas.91.5.1819 Kim, 2017, DDR2 controls the epithelial-mesenchymal-transition-related gene expression via c-Myb acetylation upon matrix stiffening, Sci. Rep., 7, 6847, 10.1038/s41598-017-07126-7 M. Cario, DDR1 and DDR2 in skin. Cell Adh Migr. 2018 Aug;1–8. Borza, 2018, Discoidin Domain Receptor 2, a potential therapeutic target in lung fibrosis, Am. J. Respir. Cell Mol. Biol., 59, 277, 10.1165/rcmb.2018-0161ED Morales, 2005, Expression of discoidin domain receptor 2 (DDR2) in the developing heart, Microsc. Microanal., 11, 260, 10.1017/S1431927605050518 Jia, 2018, Discoidin domain receptor 2 signaling regulates fibroblast apoptosis through PDK1/Akt, Am. J. Respir. Cell Mol. Biol., 59, 295, 10.1165/rcmb.2017-0419OC Zhao, 2016, Targeting of discoidin domain receptor 2 (DDR2) prevents myofibroblast activation and neovessel formation during pulmonary fibrosis, Mol. Ther., 24, 1734, 10.1038/mt.2016.109 Shyu, 2005, Regulation of discoidin domain receptor 2 by cyclic mechanical stretch in cultured rat vascular smooth muscle cells, Hypertension, 46, 614, 10.1161/01.HYP.0000175811.79863.e2 Li, 2015, Small molecule discoidin domain receptor kinase inhibitors and potential medical applications, J. Med. Chem., 58, 3287, 10.1021/jm5012319 Zhang, 2011, An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation, J. Bone Miner. Res., 26, 604, 10.1002/jbmr.225 Mehta, 2021, Complex roles of discoidin domain receptor tyrosine kinases in cancer, Vol. 23, 1497 Vogel, 2006, Sensing extracellular matrix: An update on discoidin domain receptor function, Cell. Signal., 18, 1108, 10.1016/j.cellsig.2006.02.012 Housman, 2014, Drug Resistance in Cancer: An Overview, Cancers (Basel)., 6, 1769, 10.3390/cancers6031769 Qi, 2016, Heteroplasmy of mutant mitochondrial DNA A10398G and analysis of its prognostic value in non-small cell lung cancer, Oncol Lett., 12, 3081, 10.3892/ol.2016.5086 C. Reger de Moura, M. Battistella, A. Sohail, A. Caudron, J.P. Feugeas, M. Podgorniak, et al., Discoidin domain receptors: A promising target in melanoma. Pigment Cell Melanoma Res. 2019 Jul 22;pcmr.12809. Xie, 2016, DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition, Tumor Biology., 37, 12049, 10.1007/s13277-016-5070-6 Hur, 2017, Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma, BMC Cancer., 17, 87, 10.1186/s12885-017-3051-9 Sun, 2021, Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion, Nature, 599, 673, 10.1038/s41586-021-04057-2 Vyas, 2022, The extracellular matrix and immunity: breaking the old barrier in cancer, Trends Immunol., 43, 423, 10.1016/j.it.2022.04.004 Rammal, 2016, Discoidin Domain Receptors: Potential Actors and Targets in Cancer, Front. Pharmacol., 14, 7 M. Azemikhah, H.A. Ashtiani, M. Aghaei, H. Rastegar, Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues. Res Pharm Sci. 10(4):356–63. Zhang, 2013, The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis, Nat. Cell Biol., 15, 677, 10.1038/ncb2743 Hammerman, 2011, Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer, Cancer Discov., 1, 78, 10.1158/2159-8274.CD-11-0005 Rikova, 2007, Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer, Cell, 131, 1190, 10.1016/j.cell.2007.11.025 Davies, 2005, Somatic mutations of the protein kinase gene family in human lung cancer, Cancer Res., 65, 7591, 10.1158/0008-5472.CAN-05-1855 Ding, 2008, Somatic mutations affect key pathways in lung adenocarcinoma, Nature, 455, 1069, 10.1038/nature07423 C. Thiede, C. Steudel, B. Mohr, M. Schaich, U. Schä, U. Platzbecker, et al., Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 2002. Chiaretti, 2005, Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation, Clin. Cancer Res., 11, 7209, 10.1158/1078-0432.CCR-04-2165 M.H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, et al., Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. 2008. Loriaux, 2008, High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia, Blood, 111, 4788, 10.1182/blood-2007-07-101394 Noordeen, 2006, A Transmembrane leucine zipper is required for activation of the dimeric receptor tyrosine kinase DDR1, J. Biol. Chem., 281, 10.1074/jbc.M603233200 Xu, 2014, Normal activation of discoidin domain receptor 1 mutants with disulfide cross-links, insertions, or deletions in the extracellular juxtamembrane region: Mechanistic implications, J. Biol. Chem., 289, 13565, 10.1074/jbc.M113.536144 Rudd, 2014, Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1, BMC Cancer., 14, 10.1186/1471-2407-14-884 Al-Kindi, 2014, A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking, BMC Med. Genet., 15, 10.1186/1471-2350-15-42 Bargal, 2009, Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications, Am. J. Hum. Genet., 84, 80, 10.1016/j.ajhg.2008.12.004 Imielinski, 2012, Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing, Cell, 150, 10.1016/j.cell.2012.08.029 Hanson, 2019, What makes a kinase promiscuous for inhibitors?, Cell Chem Biol., 26, 390, 10.1016/j.chembiol.2018.11.005 A. Torkamani, N. Kannan, S.S. Taylor, N.J. Schork, Congenital disease SNPs target lineage specific structural elements in protein kinases, Proc. Natl. Acad. Sci. 2008 Jul 1;105(26). Simard, 2009, High-throughput screening to identify inhibitors which stabilize inactive kinase conformations in p38α, J. Am. Chem. Soc., 131, 10.1021/ja907795q Richters, 2014, Identification of type II and III DDR2 inhibitors, J. Med. Chem., 57, 4252, 10.1021/jm500167q O’Hare, 2009, AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance, Cancer Cell, 16 Müller, 2017, Ponatinib in chronic myeloid leukemia (CML): Consensus on patient treatment and management from a European expert panel, Crit. Rev. Oncol. Hematol., 120, 10.1016/j.critrevonc.2017.10.002 Day, 2008, Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib, Eur. J. Pharmacol., 599 Canning, 2014, Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors, J. Mol. Biol., 426, 2457, 10.1016/j.jmb.2014.04.014 Pitini, 2013, Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia, Lung Cancer., 82, 171, 10.1016/j.lungcan.2013.07.004 Canning, 2014, Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors, J. Mol. Biol., 426, 2457, 10.1016/j.jmb.2014.04.014 Jeitany, 2018, Inhibition of DDR 1- BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer, EMBO Mol. Med., 10, 10.15252/emmm.201707918 Cowan-Jacob, 2007, Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia, Acta Crystallogr. D Biol. Crystallogr., 63, 80, 10.1107/S0907444906047287 Blay, 2011, Nilotinib: A novel, selective tyrosine kinase inhibitor, Semin. Oncol., 38, S3, 10.1053/j.seminoncol.2011.01.016 Beauchamp, 2014, Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss, Mol. Cancer Ther., 13, 475, 10.1158/1535-7163.MCT-13-0817 Grither, 2018, Inhibition of tumor–microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain, Proc. Natl. Acad. Sci. U S A., 115, E7786, 10.1073/pnas.1805020115 Siddiqui, 2009, Actinomycin D identified as an inhibitor of discoidin domain receptor 2 interaction with collagen through an insect cell-based screening of a drug compound library, Biol. Pharm. Bull., 32, 136, 10.1248/bpb.32.136 Brunner, 2013, Treatment-related toxicities in a phase II trial of dasatinib in patients with squamous cell carcinoma of the lung, J. Thoracic Oncol., 8, 1434, 10.1097/JTO.0b013e3182a47162 Khurshid, 2012, A phase I study of dasatinib with concurrent chemoradiation for stage III non-small cell lung cancer. Front, Oncol., 2 Elkamhawy, 2021, The journey of ddr1 and ddr2 kinase inhibitors as rising stars in the fight against cancer, Int. J. Mol. Sci.. MDPI AG, 22 Hansen, 2006, Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1, Exp. Cell Res., 312, 4011, 10.1016/j.yexcr.2006.09.003 Assent, 2015, A membrane-type-1 matrix metalloproteinase (MT1-MMP) – discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells, PLoS ONE, 10, e0116006, 10.1371/journal.pone.0116006 Takai, 2018, Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers, Genes Dev., 32, 244, 10.1101/gad.301366.117 Koh, 2015, Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition, Int. J. Cancer, 136, E508, 10.1002/ijc.29154 Saby, 2019, DDR1 and MT1-MMP expression levels are determinant for triggering BIK-mediated apoptosis by 3D type I collagen matrix in invasive basal-like breast carcinoma cells, Front. Pharmacol., 3, 10 Kothiwale, 2015, Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery, Drug Discov Today., 20, 255, 10.1016/j.drudis.2014.09.025 I. Berestjuk, M. Lecacheur, A. Carminati, S. Diazzi, C. Rovera, V. Prod’homme, et al., Targeting discoidin domain receptors DDR1 and DDR2 overcomes matrix‐mediated tumor cell adaptation and tolerance to BRAF‐targeted therapy in melanoma, EMBO Mol. Med. 2022 Feb 7;14(2). Wang, 2016, Structure-based design of tetrahydroisoquinoline-7-carboxamides as selective discoidin domain receptor 1 (DDR1) inhibitors, J. Med. Chem., 59, 5911, 10.1021/acs.jmedchem.6b00140 Nada, 2022, Identification of novel discoidin domain receptor 1 (DDR1) inhibitors using E-pharmacophore modeling, structure-based virtual screening, molecular dynamics simulation and MM-GBSA approaches, Comput. Biol. Med., 1, 142 Liu, 2017, Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors, Chem. Biol. Drug Des., 89, 420, 10.1111/cbdd.12863 Gao, 2013, Discovery and optimization of 3-(2-(Pyrazolo[1,5- a ]pyrimidin-6-yl) ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors, J. Med. Chem., 56, 3281, 10.1021/jm301824k Kim, 2013, Discovery of a potent and selective ddr1 receptor tyrosine kinase inhibitor, ACS Chem. Biol., 8, 2145, 10.1021/cb400430t Terai, 2015, Characterization of DDR2 inhibitors for the treatment of DDR2 mutated nonsmall cell lung cancer, ACS Chem. Biol., 10, 2687, 10.1021/acschembio.5b00655 Wang, 2019, Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma, Eur. J. Med. Chem., 1, 671, 10.1016/j.ejmech.2018.12.015 Mo, 2020, Design and optimization of 3′-(Imidazo[1,2- a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as selective DDR1 inhibitors, ACS Med. Chem. Lett., 11, 379, 10.1021/acsmedchemlett.9b00495 Wang, 2018, Design, synthesis, and biological evaluation of 3-(Imidazo[1,2- a ]pyrazin-3-ylethynyl)-4-isopropyl- N -(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a dual inhibitor of discoidin domain receptors 1 and 2, J. Med. Chem., 61, 7977, 10.1021/acs.jmedchem.8b01045 A. Elkamhawy, Park J. Eun, N.C. Cho, T. Sim, A.N. Pae, E.J. Roh, Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies, J. Enzyme Inhib. Med. Chem. 2016 Jan 2;31(1):158–66.