China
Africa
Explore chapters and articles related to this topic
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.
Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and broad-spectrum anticancer activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ashraf K. El-Damasy, Heewon Jin, Jung Woo Park, Hyun Ji Kim, Hanan Khojah, Seon Hee Seo, Ju-Hyeon Lee, Eun-Kyoung Bang, Gyochang Keum
On the other hand, to gain certain insights about the kinase selectivity of this array of ureidobenzothiazoles, compounds 2a and 2b were tested against DDR1 (Figure 4). Discoidin domain receptors (DDR1/2) are transmembrane receptor tyrosine kinases (RTKs), activated by fibrillar collagens27. DDR1/2 and BCR-ABL share almost 61% sequence similarities in their ATP binding domains. Therefore, several BCR-ABL inhibitors like imatinib, nilotinib, and dasatinib possess potent nanomolar DDR inhibitory effects comparable to BCR-ABL28. Interestingly, compounds 2a and 2b showed 130 and 284 folds selectivity for BCR-ABL (IC50 = 1.5 and 0.7 nM, respectively) over DDR1 (IC50 = 195 and 199 nM, respectively). This observation points out the merit of these ureidobenzothiazoles over the known BCR-ABL inhibitors in achieving exceptional selectivity towards BCR-ABL.
A patent review of discoidin domain receptor 1 (DDR1) modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Discoidin Domain Receptors (DDRs) belong to a family of receptor tyrosine kinases (RTKs) that function as hubs for the initiation of signal transduction pathways. DDRs are activated by various types of triple-helical collagens which are the most abundant components of the extracellular matrix (ECM). DDRs control important aspects of cell behaviors including proliferation, migration, adhesion, and ECM remodeling. Dysregulation of DDRs has been closely linked with various human diseases, such as cancer, fibrotic disorders, and atherosclerosis [1]. Two members of this subfamily (i.e. DDR1 and DDR2) are present in the human genome [2]. Additionally, five isoforms of DDR1 (i.e. DDR1a, DDR1b, DDR1c, DDR1d, and DDR1e) have been identified to exhibit differences in the extent of glycosylation, phosphorylation, protein interactions, expression patterns, and functions [3]. DDR1a, b, and c are kinase-active, whereas DDR1d and e are kinase domain-deficient [4]. No isoform was identified for DDR2 to date. Structurally, DDRs possess a conserved extracellular domain composed of an N-terminal discoidin domain (DS), and a collagen-binding discoidin-like (DS-like) domain [3,5] and an extracellular juxtamembrane (EJXM) domain, a transmembrane domain, a large intracellular juxtamembrane (IJXM) region, and a catalytic kinase domain conferring the tyrosine kinase activity (Figure 1).
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.