Akt inhibitor

1. Application of AKT Inhibitors in Solid Tumors Akt, a serine/threonine protein kinase with antiapoptotic activity, is one of the major downstream targets of PtdIns(3,4,5)P3 signaling pathway. It contains a pleckstrin homology domain (PH domain) that specifically binds PtdIns(3,4,5)P3 on the plasma membrane. Akt phosphorylation and activation are directly determined by the level of PtdIns(3,4,5)P3 on the plasma membrane, which is regulated by PI3K.Akt consists of three isoforms: PKBα/Akt1, PKBβ /Akt2 and PKBγ/Akt3. Akt isoforms have an N-terminal PH (pleckstrin homology) domain and a kinase domain, which are separated by a 39-amino-acid hinge region. Catalytically active Akt regulates the function of numerous substrates involved in cell survival, growth, proliferation, metabolism and protein synthesis. Akt is a crucial mediator of cell survival and its deactivation is implicated in various stress-induced pathological cell death and degenerative diseases. Memorial Sloan Kettering cancer center reported that AKT1 E17K may be a target for human cancer treatment. Patients with AKT1 E17K mutations responded better to the AKT inhibitor AZD5363. The AKT1 E17K gene mutation is carcinogenic and occurs in many cancers at a low prevalence.AZD5363 is an atp-competitive, pan-akt kinase inhibitor. To determine the preliminary activity of AKT inhibitors in cancer with AKT mutations, the basket-designed study enrolled 58 patients with advanced solid tumors who were treated with AZD5363. The primary endpoint was safety, and the secondary endpoint was progression-free survival (PFS) and efficacy assessed on RECIST criteria. Most patients received tumor biopsies and plasma cell free DNA(cfDNA) collections to determine markers that predicted efficacy. The results showed that 52 patients with AKT1 E17K mutations had tumors, and the median number of previous treatment lines was 5. The median PFS was 5.5 months (95%ci 2.9~6.9 months), 6.6 months (95%ci 1.5~8.3 months) and 4.2 months (95%ci 2.1~12.8 months) in breast cancer patients, gynecological tumor patients and other solid tumors patients with estrogen receptor-positive. In exploratory biomarker analysis, the most common cause of AKT1 E17K mutant allele imbalance was the absence of replication-neutral heterozygosis in the wild allele, which was associated with longer PFS(HR=0.41, P=0.4) and the co-existence of PI3K pathway hotspot mutation (HR=0.21, P=0.45). In cfDNA, the continuous decrease of AKT1 E17K was correlated with the improvement of PFS (HR=0.18, P=0.04) and the curative effect (P=0.25). The efficacy is not limited to patients whose AKT1 E17K can be detected in pretreated cfDNA. The most common grade 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). About Creative Biolabs As a global company, Creative Biolabs have more than 200 talented and well-trained scientists located in different continents working closely with partners from the entire world to develop and produce medicines of tomorrow. Specifically, we are the established leading expert in TCR and CAR T&NK cell immune therapy development, as we offer the one-stop custom services that cover the entire new drug development pipeline. Additionally, we also offer an exclusive line of

2. ready-to-use TCR and CAR T&NK cell construction products, such as virus packaging, purification, expansion and titer determination kits. Furthermore, we have built up a unique unparalleled CAR construction and production platform for all four CAR generations.