{"id":"W4388221408","doi":"10.1158/2159-8290.cd-23-0944","title":"Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia","year":2023,"lang":"en","type":"article","venue":"Cancer Discovery","topic":"PI3K/AKT/mTOR signaling in cancer","field":"Biochemistry, Genetics and Molecular Biology","cited_by":90,"is_retracted":false,"has_abstract":true,"ca_institutions":"Paraza Pharma (Canada)","funders":"Cycle for Survival; Memorial Sloan-Kettering Cancer Center; American Society of Clinical Oncology; National Cancer Institute; Conquer Cancer Foundation; Relay Therapeutics; U.S. Department of Defense","keywords":"Allosteric regulation; Mutant; Proof of concept; Hyperinsulinemia; Class (philosophy); Chemistry; Computational biology; Mutation; Process (computing); Cancer research; Computer science; Biology; Biochemistry; Insulin; Gene; Enzyme; Programming language; Endocrinology","routes":{"ca_aff":true,"ca_fund":false,"ca_venue":false,"about_ca":false,"invisible_to_affiliation_only":false},"retraction":null,"screen":null,"direct_labels":[],"prediction":{"model_version":"codex-gemma-dda1882f352a","candidate_categories":["metaepi_narrow"],"consensus_categories":[],"category_scores_codex":[0.0002171332,0.0003022957,0.0005961757,0.00008935782,0.00005041343,0.00004810672,0.0002789023,0.0002576006,0.00001232982],"category_scores_gemma":[0.0001754277,0.0002838475,0.0002044784,0.0003242836,0.0004529752,0.00007636993,0.0003122532,0.0002258404,0.000001150286],"about_ca_system_candidate":false,"about_ca_system_consensus":false,"about_ca_system_score_codex":0.00009121205,"about_ca_system_score_gemma":0.0004927003,"about_ca_topic_candidate":false,"about_ca_topic_consensus":false,"about_ca_topic_score_codex":0.0006338892,"about_ca_topic_score_gemma":0.001349918,"domain_scores_codex":[0.9979888,0.000097717,0.0004979713,0.0007803317,0.0002539675,0.0003812313],"domain_scores_gemma":[0.9988251,0.0001947178,0.0003631701,0.000456608,0.00007829249,0.00008206486],"domain_codex":null,"domain_gemma":null,"domain_candidate":null,"domain_consensus":null,"study_design_codex":"bench_or_experimental","study_design_gemma":"bench_or_experimental","study_design_scores_codex":[0.001607116,0.0002863933,0.3511463,0.0002164373,0.0003804424,0.00002808848,0.0002812133,0.0008966852,0.6365308,0.000009229686,0.0009304789,0.007686789],"study_design_scores_gemma":[0.001444526,0.000456969,0.1216327,0.0003034194,0.00007073316,0.000002753488,0.0001475983,0.0004077049,0.8744792,0.00005819913,0.0006508935,0.000345315],"study_design_candidate":"bench_or_experimental","study_design_consensus":"bench_or_experimental","genre_codex":"empirical","genre_gemma":"empirical","genre_scores_codex":[0.9940668,0.003163231,0.0004206429,0.0001292402,0.0008380046,0.0004014446,0.0009034589,0.00001696078,0.00006022624],"genre_scores_gemma":[0.9974638,0.00144482,0.00007016707,0.00007523024,0.0005316135,0.00009624117,0.00009971221,0.00005134686,0.0001671199],"genre_candidate":"empirical","genre_consensus":"empirical","teacher_disagreement_score":0.2379484,"threshold_uncertainty_score":0.9999614,"prediction_status":"machine_predicted_unvalidated"},"machine_scores":{"provisional":true,"baseline":true,"maturity_gate_passed":false,"score_opus":0.02614622283963229,"score_gpt":0.3036818850708201,"score_spread":0.2775356622311878,"validation_status":"score_only:v0-immature-baseline","note":"Baseline scores from an immature model (maturity gate not passed). Scores rank; they never assert a category."}}