Drug discovery

Exploring the kinome to unlock new possibilities

With our sights set on discovery, Aclaris is currently exploring the kinome, a subset of the human genome that consists of a collection of approximately 518 protein kinases, one of the largest of all human gene families, and a key control point in cell behavior.

Classified into eight major groups based on their structural similarity to each other, kinases are key regulators of cell function for many cell processes. By transferring phosphates to other molecules, kinases can induce a cellular response to environmental cues. Dysregulation and/or mutations in kinases can disrupt normal cell signaling and lead to diseases ranging from diabetes to cancer, making them important targets for drug development.

Currently, there are a number of approved kinase inhibitors on the market, such as Xeljanz® (tofacitinib citrate), Gleevec® (imatinib mesylate), and Tarceva® (erlotinib). However, these drugs only target a small fraction of the kinome, with many clinically relevant kinases lacking validated inhibitors.

We’re focused on the design and development of kinase inhibitors that target key enzymes involved in chronic inflammation, autoimmune disease, or the regulation of cancer growth, survival and metastasis.

KINect™ platform: revelationary insights from proprietary discoveries

Our proprietary KINect™ platform accelerates the identification of drug candidates through a unique combination of our proprietary chemical library of kinase inhibitors, our expertise in structure-based drug design, and our custom kinase assays.

Central to the KINect™ platform is our novel chemical library of several hundred compounds specifically designed to target non-catalytic cysteine residues near the ATP binding site of more than 300 kinases.

Using powerful drug modeling software, we are able to elaborate the structure of viable drug-like compounds culled from our library to optimize reversible binding to the target kinase and allow them to selectively form a covalent bond with the cysteine residue near the ATP site on the specific kinase target.

We then assess the function of the newly created drug candidates with physiologically relevant custom assays that effectively translate to human diseases.

drug-discovery-kinect-platform.png#asset:191

The KINect™ platform allows us to discover novel drug candidates in a fraction of the time of traditional approaches – 1-2 months to identify and optimize drug candidates that bind to a target of interest versus more than six months to years for traditional approaches that lack a tailored library.

The covalent inhibitors we generate have the potential to overcome kinome selectivity and biochemical inefficiency issues faced by other approaches for validated kinase targets.

The covalent inhibitors we generate have the potential to overcome kinome selectivity and biochemical inefficiency issues faced by other approaches.

The KINect™ platform places us at the forefront of innovation. It’s redefining what’s possible in the discovery and development of new compounds and new approaches to treating patients with severe and debilitating autoimmune and inflammatory diseases. We are elevating expectations in the dermatology and immunology space.

  • Joseph Monahan, Ph.D.,
    Executive Vice President, Research and Development of Aclaris

Preclinical compounds

ATI-450 – MK-2 pathway inhibitor oral
Potential therapeutic targets: psoriasis, psoriatic arthritis, rheumatoid arthritis, cryopyrin-associated periodic syndromes, pyoderma gangrenosum, inflammatory bowel disease
Next milestone: complete IND enabling preclinical studies

ATI-450 is a novel MK-2 pathway inhibitor and will be studied in relation to regulation of TNF-α and IL-1β via the p38/MK-2 kinase pathway. The p38/MK-2 pathway is a transducer of inflammation, and selective inhibitors of the MK-2 pathway are being investigated for their potential ability to block inflammatory cytokine production and activity and thereby restore balance to the body’s immune system. MK-2 inhibitors have the potential to treat patients with a variety of autoimmune diseases.

This compound is being developed as an oral alternative to anti-TNF/IL-1 biologics.

ATI-1777 - JAK1/JAK3 inhibitor soft topical
Potential therapeutic targets: atopic dermatitis, vitiligo, and alopecia areata
Next milestone: complete IND-enabling preclinical studies

Soft JAK inhibitors are topically applied and active in the skin, but will be rapidly metabolized and inactivated when they enter the bloodstream, which may result in significantly reduced systemic exposure. The JAK family of kinases are a subgroup of non-receptor tyrosine kinases that are essential in transducing signals originating from cytokine receptors, and whose enzymatic activity is essential for the biological activity of the cytokines in the immune system. JAK inhibitors may be useful for treating inflammatory and autoimmune disorders.

Interleukin-2-inducible T cell kinase (ITK) inhibitor / JAK 3 inhibitor oral
Potential therapeutic targets: psoriasis, inflammatory dermatoses
Next milestone: complete IND-enabling preclinical studies

ITK is an important target in immune regulation. An ITK inhibitor has significant medical potential in autoimmunity, cancer immunotherapy, leukemia, and allergic inflammation.

Currently, no oral therapies selectively target Th-17 driven diseases.

ITK inhibitors are non-receptor tyrosine kinase inhibitors of the activity of the T cell receptor pathway, thereby interfering with the development and effector function of immune system T-cells. ITK is a key signaling kinase downstream of T-cell receptors (“TCRs”) and as such, regulates IL-17 and IFNg expression. The combination of inhibiting T-cell receptors (inhibiting T-cell maturation and activation) and IL-17 production means an ITK inhibitor can be thought of as a “small molecule anti-IL-17”, but with broader immunomodulatory activity.


The brand names included throughout are the properties of their respective owners.