{"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":"metacan-v3-hybrid-931329e0061c","candidate_categories":[],"consensus_categories":[],"category_scores_codex":[0.0003109344,0.0006212228,0.0003839975,0.0002157588,0.0001046723,0.0006196345,0.0005222037,0.0004934545,0.001395753],"category_scores_gemma":[0.000289684,0.0002085901,0.0003056915,0.0001845903,0.000322004,0.0002972942,0.0002592796,0.001268233,0.0007531181],"about_ca_system_candidate":false,"about_ca_system_consensus":false,"about_ca_system_score_codex":0.0005317162,"about_ca_system_score_gemma":0.0006044607,"about_ca_topic_candidate":false,"about_ca_topic_consensus":false,"about_ca_topic_score_codex":0.000402699,"about_ca_topic_score_gemma":0.0006796945,"domain_scores_codex":[0.999874,0.00001602087,0.00000579776,0.00002525027,0.00004146929,0.00003745449],"domain_scores_gemma":[0.9999176,0.000009406573,0.00002209387,0.000006365516,0.00001531094,0.00002923346],"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":[0.001022034,0.001345074,0.0008734397,0.0004539749,0.0000664193,0.0005697217,0.00008354795,0.004692873,0.9118854,0.001831577,0.002949431,0.07422645],"study_design_scores_gemma":[0.001489536,0.01282186,0.002017788,0.00006800792,0.0001821084,0.00249219,0.00006768195,0.008569447,0.9329082,0.0007644328,0.03856888,0.00004996074],"study_design_candidate":"bench_or_experimental","study_design_consensus":"bench_or_experimental","genre_codex":"empirical","genre_gemma":"empirical","genre_scores_codex":[0.9176751,0.01561628,0.04247378,0.002089551,0.0002957295,0.001183303,0.003205557,0.001192499,0.01626816],"genre_scores_gemma":[0.9705019,0.007554301,0.01368535,0.0006618048,0.00004317749,0.0002875307,0.002143808,0.00007613692,0.005045936],"genre_candidate":"empirical","genre_consensus":"empirical","teacher_disagreement_score":0.001395753,"threshold_uncertainty_score":0.004669309,"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."}}