The AKT pathway is one of the most commonly dysregulated pathways in cancer, making it an attractive target for cancer therapy. ARQ 751 is an orally available, highly selective, next generation pan-AKT (protein kinase B) inhibitor that potently inhibits AKT1, 2 and 3 isoforms. A Phase 1 biomarker driven trial in advanced solid tumors with AKT, PI3K and PTEN mutations commenced in mid-2016. ARQ 751 has demonstrated inhibition of tumor growth and downstream AKT signaling in vivo in tumors whose growth is driven by these targets. ARQ 751 publications support AKT1 as a viable target in oncology and rare diseases.
ARQ 751 is a highly potent and selective allosteric AKT inhibitor that suppresses the AKT pathway via two modes of action. First, it binds to the inactive form of AKT and prevents membrane localization and full AKT activation. Second, it also directly inhibits the membrane associated active form of AKT. ARQ 751 was designed to be more potent and selective than miransertib, with a wider therapeutic index and predictable PK.
The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications. Preclinical research has demonstrated that ARQ 751 potently and selectively inhibits both the active and inactive forms of AKT, with potent anti-tumor activity demonstrated in PI3K/AKT driven tumor models.
The prevalence of AKT1 mutations in cancer varies from 1-6% depending on tumor types. The tumor types with the highest prevalence of AKT1 mutations are breast, bladder, endometrial, ovarian and cervical cancers. An open label dose escalation Phase 1a/1b trial is currently ongoing with the key objectives of establishing safety and recommended Phase 2 dosing is currently being conducted in patients with advanced solid tumors with molecularly defined AKT, PI3K, or actionable PTEN mutations. This trial conducted at MD Anderson Cancer Center in Houston, Texas will also look for signals of preliminary anti-tumor activity. Phase 1a results are expected in 2H 2018 followed by the initiation of an expansion cohort. A Phase 2 trial is expected to begin in 2019.