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Homology of Nonrepeated DNA Sequences in Phylogeny of Fungal Species
Published in S. K. Dutta, DNA Systematics, 2019
The 5′ untranscribed regions in another multigene family, the discoidin I gene, are also conserved since they share considerable homology.44 It is believed that these genes also arose by duplication of the original gene. The occurrence of multiple copies of genes in higher organisms thus, would provide greater flexibility and selective advantage over prokaryotes in the sense that the organism would survive mutation in a functional gene.
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.
Success stories of AI in drug discovery - where do things stand?
Published in Expert Opinion on Drug Discovery, 2022
Kit-Kay Mak, Madhu Katyayani Balijepalli, Mallikarjuna Rao Pichika
Generative Adversarial Networks (GANs) are commonly used to generate images with specific properties. A new GAN, Generative Tensorial Reinforcement Learning (GENTRL), was developed by Insilico Medicine for de novo small-molecule design [58]. Using this model, six novel and potent discoidin domain receptor 1 (DDR1) inhibitors were designed, out of which four were synthesized and tested their activity in biochemical and cell-based assays. Two were shown the most potent activity, out of which one compound (the structure is shown in Figure 1) has demonstrated promising pharmacokinetics in mice. The whole process took only less than two months, which usually requires about 2–3 years following the traditional approach. DDR1 is a kinase receptor, and it is reported to be an attractive therapeutic target for fibrosis [59]. The experimental validation of GENTRL should pave the way to design drugs against other targets and thus may improve the pharma R&D efficiency. Thomas Blaschke et al. [60] have developed REINVENT, an open-source Python application for de novo generation of the most promising small molecules for a given biological target. REINVENT was developed using the concepts of reinforcement learning and transfer learning. It is made freely available to the researchers via https://github.com/MolecularAI/ReinventCommunity.
X-linked peripheral retinoschisis without macular involvement: a case series with RS1 genetic confirmation
Published in Ophthalmic Genetics, 2020
Logan M. Smith, Linda A. Cernichiaro-Espinosa, Craig A. McKeown, Mustafa Tekin, Byron L. Lam, John Chiang, Jonathan F. Russell, Audina M. Berrocal
While the specific mutations leading to macular-sparing retinoschisis were not reported in Fahim et al.’s study, our novel mutation,, as well as the mutation reported by Eadie et al., is present in Exon 4. The mutation reported by Eadie et al. falls in the discoidin-1 sequence which has been heavily implicated in cell-cell adhesion (9). The novel mutation we discovered is in close approximation to the discoidin-1 domain at the 84th codon of the RS1 domain, which has not typically been implicated in cell-cell adhesion. Our mutation involves the introduction of a cysteine, which could interfere with the formation of intramolecular disulfide bridges normally occurring in the nearby discoidin domain resulting in the retention of retinoschisin in the endoplasmic reticulum due to abnormal protein architecture and compromised function (9). Our genetic analysis from the Molecular Vision Laboratory reported that this mutation is probably damaging by PolyPhen-2 with the highest score of 1.0, implying reasonably high confidence that it is disease causing. Another observation is that retinoschisin has been shown to play a role in the adaptation of rhodopsin-mediated signaling, with rhodopsin being more heavily expressed in rods rather than cones. Mutations in Exon 4 near the discoidin-1 domain could affect function rods to a greater degree than Müller cell function. Because rods are the predominant photoreceptive cell in the periphery, mutations in retinoschisin could affect rod function to a greater extent leading to loss of adhesion or possibly cell death and formation of cystic peripheral cavities.