ARQ 751 is an investigational, orally available, selective, next generation pan-AKT inhibitor that potently inhibits AKT1, 2 and 3 isoforms. With certain properties distinct from ARQ 092, this second clinical-stage AKT inhibitor could provide development options for the Company as it pursues indications in oncology and rare diseases. A Phase 1 biomarker driven trial in cancers with AKT 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 suppresses the AKT pathway via two modes of action. First, by binding to the inactive form of AKT, ARQ 751 prevents membrane localization and full AKT activation. Second, ARQ 751 also directly inhibits the membrane associated active form of AKT.
The AKT1 mutation is believed to play a role in a number of cancers and rare over-growth diseases, such as Proteus syndrome.
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. Pre-clinical research has demonstrated that ARQ 751 potently and selectively inhibits both the active and inactive forms of AKT.
A landmark discovery by researchers from the National Human Genome Research Institute demonstrated that a somatic mutation in the AKT1 oncogene, which carries the set of instructions to produce the AKT1 kinase, causes Proteus syndrome. A point mutation – a single-letter “misspelling” in the DNA of the genetic code — in the AKT1 gene activates the tissue growth characteristic of Proteus syndrome.
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.
We are currently collaborating with the National Human Genome Research Institute of the NIH on a clinical trial investigating ARQ 092 as a potential treatment for Proteus syndrome, a rare overgrowth disorder caused by a mutation in the AKT1 gene. Other rare diseases in which AKT plays a potentially significantly role include CLOVES syndrome and Cowden syndrome, both of which are characterized by non-cancerous overgrowths of tissue. These and other rare diseases driven by AKT1 dysregulation may present an opportunity for ARQ 751.
Identifier on clinicaltrials.gov: NCT02761694