JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors

Abstract

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS G12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS G12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS G12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036

“…Thus, discovering small-molecule therapeutics by targeting KRAS G12C has been a key focus area in cancer research for the last few decades . Recently, several small molecules, including U.S. Food and Drug Administration (FDA) approved sotorasib and adagrasib and clinical stage ARS-2102, JDQ443, and BI-0474, have been developed as KRAS G12C inhibitors to treat cancer patients. Meanwhile, GDC-6036 is a highly potent and selective small-molecule KRAS G12C covalent inhibitor discovered at Genentech and is currently in late-stage clinical development (Figure ).…”

Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors

“…To determine the reactivities of the synthesized compounds with GSH, a set of compounds ( 2d , 2e , 4n , and 4o ) were incubated with GSH in PBS, and the compounds alongside the GSH adducts were detected via liquid chromatography–mass spectrometry (LC–MS/MS) after incubating for 24 h. Compound 4n containing terminal alkynes as Michael acceptors demonstrated strong GSH binding activities; however, the amide derivatives, namely, acrylamide and butynoic amide ( 2d , 2e , and 4o ) exhibited relatively lower GSH binding activities compared with that of 1 (Table ). We speculated that utilizing aliphatic linkers would remove the conjugative effects of aromatic systems to reduce the intrinsic chemical reactivity of the acrylamide …”

“…We speculated that utilizing aliphatic linkers would remove the conjugative effects of aromatic systems to reduce the intrinsic chemical reactivity of the acrylamide. 29 Additionally, we evaluated the stability of certain compounds in rat whole blood (Figure 4). Compared with lead 1, the prototype of compound 4n decreased quickly, probably due to the high reactivity of the terminal alkyne group.…”

Recent progress in targeted therapy for non-small cell lung cancer

“…Additionally, adagrasib showed a therapeutic effect on NSCLC with intracranial metastasis (Punekar et al, 2022). With promising preliminary results from ongoing Phase Ib/II clinical trials, JDQ443 is a covalent KRAS G12C inhibitor that is now undergoing clinical development (Lorthiois et al, 2022). Several other KRAS G12C inhibitors are in clinical trials and are expected to show positive therapeutic outcomes.…”