Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c01805
Abstract
Werner syndrome helicase (WRN) has emerged as a compelling therapeutic target for microsatellite instability-high (MSI-H) cancers, owing to its selective dependency on the helicase activity of WRN. Despite the inherent challenges in targeting helicases, our chemoproteomics approach enabled the identification of compounds that covalently engage C727 within an allosteric pocket of WRN, thereby inhibiting its ability to unwind DNA. Through optimization of each molecular component, particularly focusing on the vinyl sulfone warhead and C2 substitution at the pyrimidine core, an optimal balance of intrinsic reactivity, inhibitory potency, and metabolic stability was achieved, culminating in the identification of VVD-214/RO7589831. This process underscored the tunability of the vinyl sulfone warhead and its effectiveness in covalent drug discovery. VVD-214 induced tumor regression in MSI-H colorectal cancer models and is being evaluated as a promising therapeutic candidate for MSI-H cancers.
Discovery and Optimization of a Novel Series of Pyrazolopyrimidines as Spermine Oxidase Inhibitors
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c01449
Abstract
Spermine oxidase (SMOX) is associated with pathological processes in cancer initiation and progression, driving interest in the search for SMOX inhibitors. Currently available inhibitors exhibit moderate activity and limited selectivity toward other polyamine-metabolizing enzymes such as polyamine oxidase (PAOX), underscoring the urgent need for potent and selective inhibitors of SMOX. This study focuses on the optimization of a series of pyrazolopyrimidines, leading to the discovery of JNJ-9350 as a potent inhibitor of human SMOX (hSMOX) with unprecedented selectivity over other polyamine enzymes such as hPAOX. Importantly, JNJ-9350 displays remarkable intracellular target engagement and inhibition in cellular assays, positioning JNJ-9350 as a suitable tool compound for cellular experiments to further validate the potential of SMOX inhibitors as anticancer therapeutics.
Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02412
Abstract
NLRP3 is a molecular sensor present in innate immune cells which recognizes a variety of danger signals such as MSU, ATP, or Aβ. Upon activation, it seeds a protein complex termed the inflammasome, which leads to secretion of the proinflammatory cytokines IL-1β and IL-18 and initiates pyroptotic cell death. NLRP3 inflammasome activation has been associated with a wide range of diseases including atherosclerosis, gout, and cancer. In this publication, we describe the replacement of the phenol moiety with indoles in the recently described pyridazine scaffold. This replacement required a shift of the hydrogen bond donor from the “ortho” to the “meta” position, relative to the pyridazine ring. Initial indole analog 7 demonstrated a robust in vivo IL-1β inhibition, but also a significant hERG inhibition. Decreasing lipophilicity led to the discovery of NP3-742, demonstrating a favorable overall profile including diminished hERG inhibition and in vivo efficacy in a mouse peritonitis model.
