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Ref Type Journal Article
PMID (30858154)
Authors Weisner J, Landel I, Reintjes C, Uhlenbrock N, Trajkovic-Arsic M, Dienstbier N, Hardick J, Ladigan S, Lindemann M, Smith S, Quambusch L, Scheinpflug R, Depta L, Gontla R, Unger A, Müller H, Baumann M, Schultz-Fademrecht C, Günther G, Maghnouj A, Müller MP, Pohl M, Teschendorf C, Wolters H, Viebahn R, Tannapfel A, Uhl W, Hengstler JG, Hahn SA, Siveke JT, Rauh D
Title Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 79 9 2019 05 01 2367-2378 Cancer Res
URL
Abstract Text Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. SIGNIFICANCE: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Borussertib Borussertib 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Borussertib Akt1 Inhibitor 7 Borussertib is a covalent-allosteric inhibitor of AKT1, which reduces downstream signaling and potentially decreases tumor growth (PMID: 30858154).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545K breast cancer sensitive Borussertib Preclinical - Cell culture Actionable In a preclinical study, borussertib inhibited AKT signaling and proliferation of a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 30858154). 30858154
PIK3CA K111N breast cancer sensitive Borussertib Preclinical - Cell culture Actionable In a preclinical study, borussertib inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 30858154). 30858154
PIK3CA H1047R breast cancer sensitive Borussertib Preclinical - Cell culture Actionable In a preclinical study, borussertib inhibited proliferation of a breast cancer cell line harboring PIK3CA H1047R in culture (PMID: 30858154). 30858154
PTEN L108R breast cancer sensitive MK2206 Preclinical - Cell culture Actionable In a preclinical study, MK-2206 inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154). 30858154
PTEN L108R breast cancer sensitive Borussertib Preclinical - Cell culture Actionable In a preclinical study, borussertib inhibited AKT signaling and proliferation and increased apoptosis in a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154). 30858154
PTEN L108R breast cancer sensitive Capivasertib Preclinical - Cell culture Actionable In a preclinical study, Truqap (capivasertib) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154). 30858154
PTEN L108R breast cancer sensitive Ipatasertib Preclinical - Cell culture Actionable In a preclinical study, Ipatasertib (GDC-0068) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154). 30858154
PTEN L108R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, Miransertib (ARQ092) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154). 30858154