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Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

Protein-data-bank , Cancer-cell-line-encyclopedia , Extended-data , Supplementary-information , Extended-data-table , Horizon-oncosignature , Supplementary-table ,

Researchers shed light on the molecular causes of different functions of opioid receptors

Researchers shed light on the molecular causes of different functions of opioid receptors
medicalxpress.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from medicalxpress.com Daily Mail and Mail on Sunday newspapers.

China , Jiawei-zhao , Brian-kobilka , Matthias-elgeti , Institute-for-drug-discovery , Protein-data-bank , Stanford-university , Leipzig-university , Drug-discovery ,

Brown researchers leverage AI to predict protein conformations

Brown researchers leverage AI to predict protein conformations
browndailyherald.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from browndailyherald.com Daily Mail and Mail on Sunday newspapers.

Brenda-rubenstein , George-lisi , Protein-data-bank , Monteiro-da-silva ,

The Long Read: The AI revolution

The Long Read: The AI revolution
esrf.fr - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from esrf.fr Daily Mail and Mail on Sunday newspapers.

Switzerland , Sweden , United-kingdom , Germany , London , City-of , Stockholm , German , Swiss , Marius-retegan , Vincent-favre-nicolin , Jon-cartwright

When AI Meets Biology

When AI Meets Biology
miragenews.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from miragenews.com Daily Mail and Mail on Sunday newspapers.

Kyoto , Japan , Petr-simecek , Lr-wolfgang-huber , Emma-lundberg , Oliver-stegle , Anna-kreshuk , Eva-klimentov , Mohammed-alquraishi , Central-european-institute-of-technology , Protein-data-bank , Central-european-institute-of-technology-masaryk-university

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985). RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

Protein-data-bank , Extended-data , Extended-data-table , Extended-data-tables ,

The Long Read: The AI revolution

The Long Read: The AI revolution
esrf.fr - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from esrf.fr Daily Mail and Mail on Sunday newspapers.

United-kingdom , Switzerland , Stockholm , Sweden , Germany , London , City-of , German , Swiss , Alexandra-pacureanu , Emmanuel-burtin , Vincent-favre-nicolin

Iambic Rhythm: AI Drug Developer Enters the Clinic, Targeting HER2 Cancers

Iambic Rhythm: AI Drug Developer Enters the Clinic, Targeting HER2 Cancers
genengnews.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from genengnews.com Daily Mail and Mail on Sunday newspapers.

United-states , La-jolla , California , San-diego , American , Fred-manby , Kimberly-powell , Tom-miller , Genentech , Life-sciences , California-institute-of-technology-caltech , Protein-data-bank

Bridging structural and cell biology with cryo-electron microscopy

Most life scientists would agree that understanding how cellular processes work requires structural knowledge about the macromolecules involved. For example, deciphering the double-helical nature of DNA revealed essential aspects of how genetic information is stored, copied and repaired. Yet, being reductionist in nature, structural biology requires the purification of large amounts of macromolecules, often trimmed off larger functional units. The advent of cryogenic electron microscopy (cryo-EM) greatly facilitated the study of large, functional complexes and generally of samples that are hard to express, purify and/or crystallize. Nevertheless, cryo-EM still requires purification and thus visualization outside of the natural context in which macromolecules operate and coexist. Conversely, cell biologists have been imaging cells using a number of fast-evolving techniques that keep expanding their spatial and temporal reach, but always far from the resolution at which chemistry can be understood. Thus, structural and cell biology provide complementary, yet unconnected visions of the inner workings of cells. Here we discuss how the interplay between cryo-EM and cryo-electron tomography, as a connecting bridge to visualize macromolecules in situ, holds great promise to create comprehensive structural depictions of macromolecules as they interact in complex mixtures or, ultimately, inside the cell itself. The interplay between cryo-electron microscopy and cryo-electron tomography to define complex macromolecular assemblies and visualize them in situ is explored.

South-korea , Han , Protein-data-bank , Pdb-consortium , Dn-software , Schwartz , Young , Allard , Protein-data , Trends-cell-biol , Cell-biol

ESRF's high-pressure freezing laboratory for macromolecular crystallography

ESRF's high-pressure freezing laboratory for macromolecular crystallography
esrf.fr - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from esrf.fr Daily Mail and Mail on Sunday newspapers.

Pressure-freezing-laboratory-for-macromolecular-crystallography , Protein-data-bank , High-pressure-freezing-laboratory , Macromolecular-crystallography ,