Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase

How to sensitize glioblastomas to temozolomide chemotherapy: a gap-centered view

“…In this regard, targeting APE1 holds a great promise. Alternatively, since WRN helicase plays an essential role in MMR-deficient cells, treatment with a WRN inhibitor ( Baltgalvis et al, 2024 ) might eliminate the emerging TMZ-resistant MMR-deficient glioblastoma cells.…”

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors ofChikungunyansP2 Cysteine Protease with Anti-alphavirus Activity

“…No single heteroatom appeared to be essential for enzyme inhibition, which suggested the absence of a specific H-bond between the heterocyclic core and the nsP2 enzyme. Importantly, none of the alternative heterocycles (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) formed cyclic byproducts arising from intramolecular cyclization onto the vinyl sulfone. Thus, several bioisosteric replacements of the pyrazole heterocycle were identified with the 3-phenyl isoxazole 10 being the most potent of these analogs for nsP2 protease and CHIKV inhibition.…”

“…7 Furthermore, the clinical development of vinyl sulfones has been demonstrated by K777 (Figure 1A), 9 a covalent cysteine protease inhibitor that was effective in animal models of Chagas disease, schistosomiasis, hookworm infection, and cryptosporidiosis and VVD-133214, a covalent WRN helicase inhibitor that was recently advanced to clinical trials for cancers with microsatellite instability. 10 One potential liability of 1a is its propensity for intramolecular cyclization to an inactive dihydropyrazolo[1,5- a ]pyrazin-4(5 H )-one, 11 which required the development of synthetic and analytical methods to ensure the exclusive synthesis of the acyclic vinyl sulfone 1a . 11 Herein, we report a detailed exploration of the structure activity of anti-alphaviral nsP2 protease inhibitors through systematic modification of three regions of the heterocyclic β-amidomethyl vinyl sulfone (Figure 1B).…”

Covalent Inhibitors: To Infinity and Beyond

“…Interestingly, as recently as May 2024, a mass spectrometry-based chemoproteomic screen out of Vividion therapeutics (acquired by Bayer AG in 2021) in collaboration with Roche identified VVD-109063 − an ATPcompetitive covalent fragment, which utilizes a vinyl sulfone electrophile to engage Cys727 in an allosteric pocket within the ATPase domain (i.e., helicase core) of WRN. 13 Structural optimization of this novel series ultimately led to difluoromethyl-pyrimidine VVD-133214, a clinical candidate which through the covalent inhibition of WRN protein results in promising in vivo efficacy in MSI-H cancers, through the induction of dsDNA breaks, DNA repair responses, G2 cell cycle arrest, and subsequently cell death. These 3 examples elegantly demonstrate the power of a covalent binder, against highly challenging protein targets.…”

“…While the WRN gene was discovered in 1996, a recently growing understanding of WRN biology, upstream signal transduction (with complex downstream effects), poorly understood implications in disease, lack of sufficient structural data, and logistical challenges in inhibitor screening have historically positioned WRN as a challenging (and at times undruggable) protein target. Interestingly, as recently as May 2024, a mass spectrometry-based chemoproteomic screen out of Vividion therapeutics (acquired by Bayer AG in 2021) in collaboration with Roche identified VVD-109063 – an ATP-competitive covalent fragment, which utilizes a vinyl sulfone electrophile to engage Cys727 in an allosteric pocket within the ATPase domain (i.e., helicase core) of WRN . Structural optimization of this novel series ultimately led to difluoromethyl-pyrimidine VVD-133214, a clinical candidate which through the covalent inhibition of WRN protein results in promising in vivo efficacy in MSI-H cancers, through the induction of dsDNA breaks, DNA repair responses, G2 cell cycle arrest, and subsequently cell death.…”