Blog of Signaling Pathways

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction

24 views | Jan 27 2024

The discovery of MRTX0902, a potent SOS1 binder disrupting the SOS1:KRASG12C interaction and its synergistic effect with MRTX849, targeting GDP-loaded KRASG12C, presents a promising combined strategy for enhanced antitumor activity in KRAS-driven cancers. [Read the Full Post]

Lysosomes, caspase-mediated apoptosis, and cytoplasmic activation of P21, but not cell senescence, participate in a redundant fashion in embryonic morphogenetic cell death

35 views | Jan 27 2024

This study employing micromass cultures reveals a complex interplay of apoptotic events and cellular changes during tissue remodeling, challenging the conventional association of SA-β-Gal positivity with cell senescence in developmental processes. [Read the Full Post]

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors

30 views | Jan 27 2024

The clinical trials combining GDC-1971, a SHP2 inhibitor, with divarasib (GDC-6036), a KRAS G12C inhibitor, represent a promising strategy for targeting RAS-driven MAPK signaling in solid tumors harboring KRAS G12C mutations. [Read the Full Post]

Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy

21 views | Jan 27 2024

NVP-DKY709, a selective molecular glue degrader of IKZF2, shows promise as an immune-enhancing agent for cancer immunotherapy by specifically targeting regulatory T cells and T-effector cells, potentially altering tumor growth and improving immune responses in preclinical models. [Read the Full Post]

The relationship between discrimination, alcohol use severity, and PTSD symptoms among Latinx heavy drinkers

33 views | Jan 27 2024

This study underscores how discrimination's impact on alcohol use severity among Latinx adults is intricately connected to PTSD symptoms, highlighting the need for culturally adapted interventions tailored to those with higher PTSD symptomatology. [Read the Full Post]

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

17 views | Jan 26 2024

The discovery of MM3122, a covalent ketobenzothiazole inhibitor with potent activity against TMPRSS2 and various coronaviruses, showcasing exceptional efficacy, metabolic stability, and favorable pharmacokinetics in mice, stands as a promising breakthrough for COVID-19 treatment. [Read the Full Post]

First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antago

41 views | Jan 26 2024

Inhibiting oxidative phosphorylation via the NDUFS7 antagonist DX2-201 presents a promising and novel therapeutic strategy for pancreatic cancer, demonstrating efficacy, direct targeting of drug resistance mechanisms, and synergistic potential with metabolic and PARP inhibitors. [Read the Full Post]

CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats

26 views | Jan 26 2024

This study elucidates that CCL17 activates the CCR4/mTORC2 axis in microglia, promoting M2-like polarization and significantly ameliorating neurological deficits after subarachnoid hemorrhage. [Read the Full Post]

Structural and energetic insights into the selective inhibition of PKMYT1 against WEE1

20 views | Jan 26 2024

This comprehensive study utilizing molecular simulations and free energy calculations unveils the molecular basis behind RP-6306's binding selectivity towards PKMYT1 over WEE1, offering critical insights for the design of more effective and specific inhibitors in cancer therapy. [Read the Full Post]

Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations

45 views | Jan 26 2024

Your detailed study on BLU-945 and its analogues' enhanced binding affinities to EGFR mutants sheds critical light on potential mechanisms for combating drug resistance in NSCLC, potentially steering future drug development toward more effective treatments. [Read the Full Post]

Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches

20 views | Jan 25 2024

The study's rigorous virtual screening and molecular dynamics simulations identified promising compounds with potential to inhibit DNMT1, offering a hopeful avenue for improving sickle cell disease treatment pending further in vitro and in vivo validation. [Read the Full Post]

Antitumor effect of a small-molecule inhibitor of KRASG12D in xenograft models of mucinous appendicular neoplasms

38 views | Jan 25 2024

The profound inhibition of tumor growth in a high-grade PMP xenograft mouse model carrying a KRASG12D mutation by the small-molecule KRASG12D inhibitor MRTX1133 underscores its potent efficacy and supports its potential for clinical translation in treating PMP. [Read the Full Post]

Regulation of Photosensitivity by the Hippo Pathway in Lupus Skin

22 views | Jan 25 2024

Enhanced UVB-induced apoptosis in SLE keratinocytes is driven by overactive Hippo signaling, characterized by hypomethylation-induced WWC1 overexpression, leading to altered YAP activity and promoting cell death. [Read the Full Post]

Porphyromonas gingivalis induces an inflammatory response via the cGAS-STING signaling pathway in a periodontitis mouse model

24 views | Jan 25 2024

The study illustrates that the cGAS-STING signaling pathway is pivotal in mediating the inflammatory response induced by Porphyromonas gingivalis, potentially offering a promising target for managing chronic periodontitis. [Read the Full Post]

RGCC-mediated PLK1 activity drives breast cancer lung metastasis by phosphorylating AMPKα2 to activate oxidative phosphorylation and fatty acid oxidation

27 views | Jan 25 2024

The study reveals that RGCC overexpression drives a signaling cascade, involving PLK1 and AMPKα2, enhancing metabolic adaptations in TNBC cells, providing crucial insights and potential therapeutic targets for combating lung-specific metastasis in triple-negative breast cancer. [Read the Full Post]

Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects

8 views | Jan 24 2024

The discovery of iso-A11B5C1 as a muscle-specific ionizable lipid for mRNA delivery, challenging traditional immune cell transfection paradigms, redefines the criteria for effective mRNA vaccines and expands the horizon for tissue-targeted therapies. [Read the Full Post]

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review

38 views | Jan 24 2024

This systematic review consolidates evidence showcasing the promising efficacy of WEE1 inhibitors in gynecological malignancies while highlighting the significance of biomarker-driven patient selection for optimizing treatment response. [Read the Full Post]

Phase II study of bemnifosbuvir in high-risk participants in a hospital setting with moderate COVID-19

14 views | Jan 24 2024

The study on bemnifosbuvir for moderate COVID-19, while not meeting its primary efficacy endpoint, demonstrated well-tolerance, absence of increased mortality, and a potential for reducing viral load, suggesting a promising avenue for further exploration in managing COVID-19 progression. [Read the Full Post]

An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex

14 views | Jan 24 2024

The modification of Bemnifosbuvir into the α-thiotriphosphate form, AT-9052-Sp, not only evades viral exonuclease-mediated resistance but also demonstrates a unique mechanism of immediate chain termination against SARS-CoV-2, offering a promising strategy for overcoming viral proofreading mechanisms in antiviral drug development. [Read the Full Post]

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer

15 views | Jan 24 2024

MRTX1719, a selective PRMT5 inhibitor, displays remarkable efficacy against MTAP-deleted cancers while sparing MTAP wild-type cells, showcasing promising therapeutic potential and early clinical success across a spectrum of malignancies. [Read the Full Post]