April 30th<\/p>\n
https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02314<\/a><\/p>\n Abstract<\/p>\n Oncogenic RAS mutations are among the most common in human cancers. To target the active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein RAS blocks effector binding, inhibiting downstream RAS signaling and tumor cell proliferation. Herein, we describe the structure-guided SAR journey that led to the discovery of daraxonrasib (RMC-6236), a noncovalent, potent tri-complex inhibitor of multiple RAS mutant and wild-type (WT) variants. This orally bioavailable bRo5 macrocyclic molecule occupies a unique composite binding pocket comprising CypA and SWI\/SWII regions of RAS(ON). To achieve broad-spectrum RAS isoform activity, we deployed an SAR campaign that focused on interactions with residues conserved between mutants and WT RAS isoforms. Concurrent optimization of potency and drug-like properties led to the discovery of daraxonrasib (RMC-6236), currently in clinical evaluation in RAS mutant advanced solid tumors (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551).<\/p>\n April 24th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02889<\/a><\/p>\n Abstract<\/p>\n Hematopoietic stem cell (HSC) mobilization is often difficult to achieve in patients suffering from multiple myeloma and non-Hodgkin\u2019s lymphoma. Granulocyte-colony stimulating factor (G-CSF) therapy alone has often not led to the desired outcomes. Herein, we describe the discovery of 7-cyclohexyl-4-hydroxy-8-oxo-N<\/i>-(pyridazin-4-ylmethyl)-7,8-dihydro-2,7-naphthyridine-3-carboxamide\u00a013<\/b>, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which was discovered by focusing on drug-like properties. Building on a previous discovery that HIF–<\/span>PH inhibitors can enhance HSC mobilization in combination with G-CSF, we optimized\u00a013<\/b>\u00a0to exhibit high PHD2 potency, improved solubility, and an optimized PK profile.\u00a013<\/b>\u00a0was effective at enhancing G-CSF-induced HSC mobilization in mice at a dose of 2 mg\/kg.<\/p>\n April 21st<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02759<\/a><\/p>\n Abstract<\/p>\n The discovery of DFV890 ((R<\/i>)-1<\/b>), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The\u00a0(R)-<\/i>enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R<\/i>)-1<\/b>), which potently inhibited IL-1\u03b2 production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R<\/i>)-1<\/b>) was also effective in an air pouch model of gout.<\/p>\n April 17th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c03067<\/a><\/p>\n Abstract<\/p>\n The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10\u201315% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets\u00a0MTAP<\/i>-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in\u00a0MTAP<\/i>-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for\u00a0MTAP<\/i>-deleted cancers and is currently in Phase I\/II clinical trials.<\/p>\n April 14th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02313<\/a><\/p>\n Abstract<\/p>\n The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRASG12C<\/sup>. To target the active state of RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation of a complex with an inhibitor, the intracellular chaperone protein CypA, and the target protein KRASG12C<\/sup>\u00a0in its GTP-bound form. The resulting tri-complex inhibits oncogenic signaling, inducing tumor regressions across various preclinical models of KRASG12C<\/sup>\u00a0mutant human cancers. Here we report structure-guided medicinal chemistry efforts that led to the discovery of elironrasib, a potent, orally bioavailable, RAS(ON) G12C-selective, covalent, tri-complex inhibitor. The investigational agent elironrasib is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), with preliminary data indicating clinical activity in patients who had progressed on first-generation inactive state-selective KRASG12C<\/sup>\u00a0inhibitors.<\/p>\n April 10th<\/p>\n https:\/\/pubs.acs.org\/doi\/abs\/10.1021\/acs.jmedchem.4c02751<\/a><\/p>\n Abstract<\/p>\n N<\/i>-Methyl-d<\/span>-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The\u00a0TCN-201<\/b>\u00a0derivatives\u00a0MPX-004<\/b>\u00a0and\u00a0MPX-007<\/b>\u00a0are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the\u00a0MPX-004<\/b>\/MPX-007<\/b>\u00a0scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound\u00a01<\/b>\u00a0was used to develop the first GluN2A NAM-based radioligand, and compound\u00a011<\/b>\u00a0showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.<\/p>\n <\/p>\n April 7th<\/p>\nDiscovery of Novel, Potent, Orally Bioavailable and Efficacious, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Hematopoietic Stem Cell Mobilization<\/span><\/h2>\n
Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor<\/span><\/h2>\n
Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with\u00a0MTAP<\/i>\u00a0Deletion<\/span><\/h2>\n
Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers<\/span><\/h2>\n
Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration<\/span><\/h2>\n
Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor<\/span><\/h2>\n