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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the molecular level, nilotinib has been shown to inhibit kinases including Bcr-Abl, Kit, Lck, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11, and ZAK. However, it does not inhibit the Src kinase, a key regulator of other tyrosine kinase proteins that influence whether cells proliferate or die. The binding of nilotinib to its target Bcr-Abl protein is energetically more favorable than that of imatinib, and it has been shown to have an approximately 20-fold increase in potency compared to imatinib in in vitro kinase inhibition and cellular proliferation assays.
Lung cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
DDR2 mutations have been identified in less than 4% of SCCs and are oncogenic, although the exact mechanism is unclear. Dasatinib, the multi-targeted TKI, has been shown to be effective against DDR2-mutant SCCs in cell lines and animal studies.24
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
In NSCLC, numerous genes involved in tumor proliferation are the target of agents currently in various stages of clinical development: EGFR, HER2 (human epidermal growth factor receptor 2), ROS1 (reactive oxygen species 1), BRAF (v-raf murine sarcoma viral oncogene homologue B1), MAPK (mitogen-activated protein kinase), c-MET (c-mesenchymal-epithelial transition), PTEN (phosphatase and tensin homolog), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha), RET (rearranged during transfection), AKT (protein kinase B) and ALK (anaplastic lymphoma kinase), among others. The activity of these onco-genic targets occurs through various pathways such as DRC-signal transduction, phosphoinositide 3-kinase-AKT-mTOR, RAS-RAF-MEK, etc. To date, there are five approved targeted therapies for treatment of advanced or metastatic NSCLC: gefitinib, erlotinib, and afatinib for EGFR mutated patients, crizotinib for ALK translocated patients and bevacizumab which currently lacks a reliable pre-treatment biomarker. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes have been demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in development and maintenance of the malignant phenotype has also provided additional therapeutic approaches. More recently, improved knowledge of tumor immunology has set the stage for promising immunotherapies in NSCLC. The main molecular alterations are listed in Table 2.2.
Understanding collagen interactions and their targeted regulation by novel drugs
Published in Expert Opinion on Drug Discovery, 2021
Marialucia Gallorini, Simone Carradori
ECM remodeling is partly regulated by DDRs through the control of metalloproteinases by integrin alpha2β1. Cell proliferation, migration, differentiation and survival are regulated by DDRs. Physiologically, DDRs are expressed in various tissues in human and mice during the early embryonic development. DDR2 is found in cells of the connective tissue while DDR1 is mostly express in epithelial and smooth muscle cells (SMCs). DDR1 undergoes phosphorylation and initiates various downstream signaling pathways, including the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase and estrogen receptor kinase signaling in vascular smooth muscle cells, upon activation by binding type I–III, V fibrillar collagens, or networking-forming collagen IV. DDR1 also modulates molecular signaling triggered by other receptors in the ECM (e.g. integrins), cytokines (e.g. TGF-β), and transmembrane receptors (e.g. Notch1) [81]. DDR2 is a key receptor in mechanosensitive cell responses such as migration and proliferation, regulating FAK levels [82]. Finally, most cancers and rheumatic and inflammatory disorders have been linked with an imbalance in DDR expression levels [83,84].
A patent review of discoidin domain receptor 1 (DDR1) modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Particularly, allosteric inhibitors targeting the extracellular domain could be considered as a new approach to specifically modulate DDR1-mediated downstream signaling. Since extracellular regions of DDR1 and DDR2 bind different collagens and share a relatively low degree of sequence identity, highly specific DDR1 or DDR2 inhibition might be achieved by utilizing this strategy. Encouragingly, a small-molecule allosteric regulator targeting the extracellular domain of DDR2 was recently discovered to exhibit good target specificity which paved a solid foundation for the discovery of new generation DDR1 inhibitors with improved target specificity [69]. PROTACs or heterobifunctional degrader molecules typically comprise an E3 ligase binding scaffold (hereafter E3-moiety), attached through a linker to another small molecule (hereafter target-moiety) that binds a target protein of interest. Recruitment of this target protein to the E3 ubiquitin ligase facilitates ubiquitination and subsequent degradation of the target protein. PROTACs represent a promising new pharmacologic modality now widely explored in chemical biology and drug discovery. The PROTAC technique can be applied in the development of DDR1 modulators, which would open a new window for targeted DDR1 therapies. The monoclonal antibody binds to a specific antigen on the cancer cell. The main advantage of antibody over kinase inhibitors is higher selectivity and safety.
Deletion of discoidin domain receptor 2 attenuates renal interstitial fibrosis in a murine unilateral ureteral obstruction model
Published in Renal Failure, 2019
Xi’an Li, Xin Bu, Fei Yan, Fuli Wang, Di Wei, Jiarui Yuan, Wanxiang Zheng, Jin Su, Jianlin Yuan
Discoidin domain receptors (DDRs), encompassing DDR1 and DDR2, are unusual in that they become autophosphorylated in response to binding collagen, in contrast to receptor tyrosine kinases (RTKs) which are predominantly activated by soluble factors [6]. DDR2 is mainly expressed in mesenchymal cells [7], encompassing multiple cell types, such as smooth muscle cells, osteoblasts, and fibroblasts [8]. The mesenchymal DDR2 expression shows highest levels in skeletal muscle, skin, kidney, and lung tissue [9]. DDR2 was demonstrated to be associated with several pathological processes including hepatic fibrosis, osteoarthritis, wound healing, and tumor metastasis [10–13]. Nevertheless, the functional role of DDR2 in renal interstitial fibrosis remains unclear.