Tatu Pantsar

Abstract B001: eIF2B Selectively Anchors and Activates Mutant KRAS4B

Hyungdong Kim, Shiqi Diao, Kwang-Jin Cho, Hyun-Ro Lee et autres

Abstract Activating mutations in KRAS occur at high frequency in colorectal, lung, and pancreatic cancers, which together account for a substantial proportion of global cancer mortality. Mutant KRAS is constitutively biased toward the GTP-bound state, driving persistent proliferative signaling, but simultaneously imposes …

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eIF2B Selectively Anchors and Activates Mutant KRAS

Hyungdong Kim, Shiqi Diao, Kwang‐Jin Cho, Hyun-Ro Lee et autres

ABSTRACT Much is known about how RAS oncoproteins regulate mRNA translation factors, but the reverse relationship, how translation factors influence RAS activity, has remained largely unexplored. At the plasma membrane (PM), Son of Sevenless (SOS) acts as the canonical guanine nucleotide exchange …

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PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

Pieter Leyssen, Christopher R. M. Asquith, Manon Gourdelier, Aditi Agrawal et autres

In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target …

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PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

Marwah Karim, Manjari Mishra, Chieh‐Wen Lo, Sirle Saul et autres

In search for broad-spectrum antivirals, we discover a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrate selective inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target …

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Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations

Renne Leini, Jonas N. Kapp, Kari Kopra, Tatu Pantsar

Over 100 co-crystal structures of KRAS switch-II pocket (SII-P) targeting inhibitors are currently available in the RCSB Protein Data Bank. These publicly available structures are invaluable tools that have led to a more in-depth understanding of KRAS SII-P pocket, which is crucial …

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Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations

Renne Leini, Jonas N. Kapp, Kari Kopra, Tatu Pantsar

Over 100 co-crystal structures of KRAS switch-II pocket (SII-P) targeting inhibitors are currently available in the RCSB Protein Data Bank. These publicly available structures are invaluable tools that have led to a more in-depth understanding of KRAS SII-P pocket, which is crucial …

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First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer

Ramona Rudalska, Jule Harbig, Michael Förster, Pascal Woelffing et autres

Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient …

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Beyond KRAS(G12C): Biochemical and Computational Characterization of Sotorasib and Adagrasib Binding Specificity and the Critical Role of H95 and Y96

Randa Mahran, Jonas N; https://orcid.org/0000-0002-7308-559X Kapp, Salla Valtonen, Allison Champagne et autres

Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers and thus have been a target of intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors have finally reached clinical practice. Sotorasib …

Beyond KRAS(G12C): Biochemical and Computational Characterization of Sotorasib and Adagrasib Binding Specificity and the Critical Role of H95 and Y96

Randa Mahran, Jonas N. Kapp, Salla Valtonen, Allison Champagne et autres

Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers and thus have been a target of intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors have finally reached clinical practice. Sotorasib …

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Bromo-substituted indirubins for inhibition of protein kinase-mediated signalling involved in inflammatory mediator release in human monocytes

Vivien Bachmann, Patrick Schädel, Jan Westhoff, Milica Perić et autres

Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen …

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Beyond KRAS(G12C): biochemical and computational characterization of sotorasib and adagrasib binding specificity and the critical role of H95 and Y96

Randa Mahran, Jonas N. Kapp, Salla Valtonen, Allison Champagne et autres

Mutated KRAS proteins are frequently expressed in some of the most lethal human cancers, thus having been a target of intensive drug discovery efforts for decades. Lately, KRAS(G12C) switch-II pocket (SII-P)-targeting covalent small molecule inhibitors have finally reached the clinical practice. Sotorasib …

fi, ch, us (code pays fourni par la source)

PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2

Marwah Karim, Manjari Mishra, Chieh‐Wen Lo, Sirle Saul et autres

In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and …

us, dk, be, fi, au (code pays fourni par la source)