ATRIN's Drug Discovery and Rapid Development Technologies
Atrin's drug discovery and development processes integrate two drug discovery platforms: ATRIZE™ and SCET™
ATRIZE™ is an innovative, high throughput detection system of cell cycle and DDR regulation. ATRIZE™ is designed to identify novel DDR treatments by sensing cell vulnerability to DNA damage. ATRIZE™ significantly reduced the time required to discover active novel treatments and their targets for Atrin's design and testing of drugs in precision cancer therapy.
SCET™ (Small Cyclic Enzyme Targeting) is a MedChem cyclization paradigm which generates potent microcyclic, proprietary and selective enzyme inhibitors. By utilizing SCET™, Atrin has created compounds with superior pharmacological profiles compared with acyclic pharmacophores.
Combining molecular oncology expertise and efficient synthesis of molecular diversity have been the key success factors of Atrin's DDR drug discovery.
Atrin's SCET approach is based on the conformational constraint of bioactive pharmacophores. A pharmacophore is a minimal- sized extended (acyclic) structure which inhibits target enzymes.
By utilizing its proprietary cyclization technology, Atrin has designed and synthesized a wide range of analogs with diverse structures and conformations against selected target enzymes. This molecular diversity represents the power of Atrin's drug discovery technology, and has enabled rapid identification of enzyme inhibitors for anticancer drug treatment.
SCET: in most cases; the bioactive pharmacophore has a flexible 3D structure. This molecular flexibility is mainly due to its extended conformation. As a consequence; the pharmacophore may adopt a wide range of conformations (in its bio-space) which may lead to nonspecific interactions with off-target enzymes. These nonspecific interactions result in less selectivity and unwanted adverse effects in the body.
The SCET approach enables the design and synthesis of novel conformationally-constrained pharmacophore-based analogs. As a result; these small cyclic analogues have more rigid structures which interact with higher affinity (potency) and specificity to the target enzyme with less nonspecific interactions. By utilizing this approach, Atrin has developed highly potent and specific anticancer drug candidates with potential broader therapeutic profiles.
After years of research, Atrin has established that cancer cells have a high dependency on ATR.
This protein kinase acts upstream of the DDR cascade, and was observed to be hyperactive in cancer cells. It became clear that the inhibition of ATR in cancer cells would be the key to destruction of cancer cells, with high selectivity.
ATRN-119 is Atrin's lead ATR inhibitor, a water soluble, orally bioavailable, highly potent and specific to ATR molecule with a potentially differentiated and broad therapeutic window, traits expected to lead to significantly fewer off-target effects versus competing ATRi.
Atrin has developed a series of ATRNs: bioactive inhibitors of ATR and other DDR targets.
ATRNs have bioactivity:
In a wide spectrum of cancers
At very low doses
With minimal or no off-targeting and potentially less clinical toxicity
With superior efficacy
With greater specificity than competing ATRi
How it works
After years of ground-breaking research into the DNA Damage and Response pathway, Atrin established that cancer cells have a high dependency on ATR. This protein kinase is found in all cells, but was observed to be hyperactive in cancer cells. It then became clear to the scientific founders of Atrin that the inhibition of the ATR in cancer cells would be new key to the destruction of cancer cells.
ATRN-119 is a small molecule targeting the ATR-mediated checkpoint response. ATR is a member of the same family of kinases as ATM, DNA-PK, and mTOR (PIK-related kinases). ATR kinase is a key cellular mediator of DNA Damage and Repair that is critical to cancer cell survival in the face of increasing DNA damage, and genomic instability, over time. ATR regulates responses to DNA replication abnormalities, and functions as a checkpoint kinase upstream of CHK1.
One of the major hurdles to the development of an effective ATR inhibitor has been off-targeting of other PIKKs. Combined inhibition of ATR together with other PIKKs, such as ATM or DNA-PKcs is extraordinarily toxic to non-cancer cells. Therefore, ATR inhibitors with such off-targeting have significant toxicity to normal tissues, which limits their dosing, and thus also their ultimate clinical value.
ATRN-119, with improved cellular potency and >2,000-fold increased specificity over ATM, is expected to become the best-in-class ATRi for these reasons. ATRN-119's highly-specific inhibition of ATR permits it to capitalize on synthetic-lethal interactions with cancer-associated mutations that do not occur in normal cells, thus minimizing toxicity to normal tissues.
The above cancer-associated mutations include ATM mutations. Any compound that targets both ATR and ATM thus forfeits any cancer selectivity rendered by ATM mutation. Therefore, we believe that the exceptional specificity of Atrin's ATR inhibitors will lead to superior clinical outcomes versus other, less selective, ATRi.
ATRN-119 is water soluble and bioavailable following oral administration, and can be used as both a single-agent and in combination therapy.