ABSTRACT
Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRASG12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Mechanistic Target of Rapamycin Complex 1 , Proto-Oncogene Proteins p21(ras)/metabolism , Cell Proliferation , TOR Serine-Threonine Kinases , Mechanistic Target of Rapamycin Complex 2 , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Cell Line, TumorABSTRACT
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Pyrazoles/pharmacology , Quinolines/pharmacology , Receptors, Notch/antagonists & inhibitors , Sulfonamides/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Animals , Area Under Curve , Basic Helix-Loop-Helix Transcription Factors/genetics , Dogs , Dose-Response Relationship, Drug , Drug Design , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gene Expression/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Homeodomain Proteins/genetics , Humans , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Chemical , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Notch/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Time Factors , Transcription Factor HES-1ABSTRACT
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Protein Precursor/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Inhibitory Concentration 50 , Mice , Mice, Inbred Strains , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Piperidines/chemistry , Sulfonamides/chemistry , Animals , Drug Discovery , Drug Stability , Microsomes, Liver/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.