ABSTRACT
Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C 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 KRASG12C 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 KRASG12C 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).
Subject(s)
Neoplasms , Proto-Oncogene Proteins p21(ras) , Animals , Humans , Mice , Disease Models, Animal , Drug Design , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Pyrazoles/pharmacology , Pyrazoles/therapeutic useABSTRACT
The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.
Subject(s)
Blood/metabolism , Caspase Inhibitors/therapeutic use , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Urea/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Caspase Inhibitors/chemical synthesis , Caspase Inhibitors/metabolism , Caspase Inhibitors/pharmacokinetics , Cell Line, Tumor , Female , Half-Life , Humans , Mice, Inbred BALB C , Mice, SCID , Microsomes, Liver/metabolism , Neoplasms/drug therapy , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Sheep , Urea/chemical synthesis , Urea/metabolism , Urea/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells.
