Abstract:Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, the signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF, and MEK have long been a focus in cancer drug discovery. In this review, we provide an overvi… Show more
“…To avoid rereviewing the topics which were covered, we refer the reader to these recent excellent publications. These include subcellular localization and considering exploiting the membrane in therapeutics (Kattan and Hancock 2020;Zhou et al 2018), mutational analysis and isoform signaling (Li et al 2018a;Munoz-Maldonado et al 2019;Prior et al 2020;Randic et al 2021), subcellular localization and tumor growth (Garcia-Ibanez et al 2020), Ras-ERK signaling (Zaballos et al 2019) and MAPK inhibition (Heppner and Eck 2021;Ullah et al 2021), isoform-specific differences in the effector binding regions (Nakhaeizadeh et al 2016), and the recent contributions from the Mark Philips lab on KRas4A reversible palmitoylation and colocalization (Amendola et al 2019) and on membrane association/colocalization (Zhou et al 2020). Isoform signaling specificity at the membrane (Nussinov et al 2018a), KRas mobility in the membrane (Nussinov et al 2019b) and nanoclustering (Nussinov et al 2019a) were also reviewed as well as genetic aspects of KRas signaling networks (Jinesh et al 2018).…”
Section: Earlier Discussion On Ras Isoformsmentioning
The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage. Here, we review some isoform-specific activities at the plasma membrane from a structural dynamic standpoint. Inspired by physics and chemistry, we recognize that understanding functional specificity requires insight into how biomolecules can organize themselves in different cellular environments. Within this framework, we suggest that isoform-specific expression may largely be controlled by the chromatin density and physical compaction, which allow (or curb) access to “chromatinized DNA.” Genes are preferentially expressed in tissues: proteins expressed in pancreatic cells may not be equally expressed in lung cells. It is the rule—not an exception, and it can be at least partly understood in terms of chromatin organization and accessibility state. Genes are expressed when they can be sufficiently exposed to the transcription machinery, and they are less so when they are persistently buried in dense chromatin. Notably, chromatin accessibility can similarly determine expression of drug resistance genes.
“…To avoid rereviewing the topics which were covered, we refer the reader to these recent excellent publications. These include subcellular localization and considering exploiting the membrane in therapeutics (Kattan and Hancock 2020;Zhou et al 2018), mutational analysis and isoform signaling (Li et al 2018a;Munoz-Maldonado et al 2019;Prior et al 2020;Randic et al 2021), subcellular localization and tumor growth (Garcia-Ibanez et al 2020), Ras-ERK signaling (Zaballos et al 2019) and MAPK inhibition (Heppner and Eck 2021;Ullah et al 2021), isoform-specific differences in the effector binding regions (Nakhaeizadeh et al 2016), and the recent contributions from the Mark Philips lab on KRas4A reversible palmitoylation and colocalization (Amendola et al 2019) and on membrane association/colocalization (Zhou et al 2020). Isoform signaling specificity at the membrane (Nussinov et al 2018a), KRas mobility in the membrane (Nussinov et al 2019b) and nanoclustering (Nussinov et al 2019a) were also reviewed as well as genetic aspects of KRas signaling networks (Jinesh et al 2018).…”
Section: Earlier Discussion On Ras Isoformsmentioning
The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage. Here, we review some isoform-specific activities at the plasma membrane from a structural dynamic standpoint. Inspired by physics and chemistry, we recognize that understanding functional specificity requires insight into how biomolecules can organize themselves in different cellular environments. Within this framework, we suggest that isoform-specific expression may largely be controlled by the chromatin density and physical compaction, which allow (or curb) access to “chromatinized DNA.” Genes are preferentially expressed in tissues: proteins expressed in pancreatic cells may not be equally expressed in lung cells. It is the rule—not an exception, and it can be at least partly understood in terms of chromatin organization and accessibility state. Genes are expressed when they can be sufficiently exposed to the transcription machinery, and they are less so when they are persistently buried in dense chromatin. Notably, chromatin accessibility can similarly determine expression of drug resistance genes.
“…The second generation (Figure ) has an αC-out binding conformation with specific selectivity for the tumor driven by the BRAF monomer to target the BRAF V600E mutant with a broad therapeutic window. As monotherapies or in combination with other targeted treatments, these inhibitors significantly improve clinical outcomes for patients with BRAF V600 mutation-driven melanoma and some solid malignancies. ,, …”
Section: Current
Insight Into Braf Inhibitorsmentioning
confidence: 99%
“…As monotherapies or in combination with other targeted treatments, these inhibitors significantly improve clinical outcomes for patients with BRAF V600 mutation-driven melanoma and some solid malignancies. 53,75,90 Dabrafenib is an ATP-competitive inhibitor of BRAF kinases was first developed under the name GSK2118436 by GlaxoSmithKline (GSK). It suppresses BRAF V600E more effectively than BRAF V600WT .…”
Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAF V600 ), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/ OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.
“…When a receptor, as with a GF, binds to an RTK, the signaling pathways are initiated. Intricate pessimistic feedback chain inhibits activation of the RTK signaling pathway by diminishing signaling from activated receptors 5 . Figure 1 Binding of Growth Factor (GF) to RTKs.…”
Malignant cancer angiogenesis has historically attracted enormous scientific attention. Although angiogenesis is requisite for a child’s development and conducive to tissue homeostasis, it is deleterious when cancer lurks. Today, anti-angiogenic biomolecular receptor tyrosine kinase inhibitors (RTKIs) to target angiogenesis have been prolific in treating various carcinomas. Angiogenesis is a pivotal component in malignant transformation, oncogenesis, and metastasis that can be activated by a multiplicity of factors (e.g., VEGF (Vascular endothelial growth factor), (FGF) Fibroblast growth factor, (PDGF) Platelet-derived growth factor and others). The advent of RTKIs, which primarily target members of the VEGFR (VEGF Receptor) family of angiogenic receptors has greatly ameliorated the outlook for some cancer forms, including hepatocellular carcinoma, malignant tumors, and gastrointestinal carcinoma. Cancer therapeutics have evolved steadily with active metabolites and strong multi-targeted RTK inhibitors such as E7080, CHIR-258, SU 5402, etc. This research intends to determine the efficacious anti-angiogenesis inhibitors and rank them by using the Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE- II) decision-making algorithm. The PROMETHEE-II approach assesses the influence of growth factors (GFs) in relation to the anti-angiogenesis inhibitors. Due to their capacity to cope with the frequently present vagueness while ranking alternatives, fuzzy models constitute the most suitable tools for producing results for analyzing qualitative information. This research’s quantitative methodology focuses on ranking the inhibitors according to their significance concerning criteria. The evaluation findings indicate the most efficacious and idle alternative for inhibiting angiogenesis in cancer.
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