DNA-SEQ Kinase Crystal Structures Library

Steps in Structure-Based Anti-Kinase Drug Discovery

Capitalizing on Being First in the World - Lessons from Gleevec ® design. DNA SEQ Inc. Crystal Structure Based Anti-Kinase Drug Discovery.


Specific inhibitor for normal kinase

Expert Knowledge of Design of Specific Inhibitors for patient Normal Kinases. Hover or click to learn more.


Inhibitor with specificity region A1 binds to the specific region A of normal kinase. Specificity of the inhibitor and its potency is important to win “the battle” with ATP.


Specific inhibitor for cancer mutated kinase

Entire patient kinome analysis to identify mutated kinases and design of specific inhibitor for mutated kinase. Hover or click to learn more.


Cancer develops an “activating mutation” in this kinase creating new specificity region B. Inhibitor is developed with another specificity feature B1 to match “the activating mutation” and to specifically inhibit this cancer activated kinase.


Specific inhibitor for patient resistance mutated kinase

Rapid virtual screen using quantum-classical hybrid computation to design specific inhibitor for patient resistance mutated kinase. Hover or click to learn more.


Patient resistance “fights off” inhibitor and results in a new mutation creating new specificity region C. New inhibitor is designed with yet another feature C1 to match the new specificity region. Cancer is transformed into a manageable chronic disease.

DNA-SEQ’s Kinase Crystal Structures Library

The worldwide pursuit of a precise crystallography-based fight against cancer was initiated with the identification of the first crystal structure of a kinase - PKA. It remains the best characterization for the emerging structural language describing the context, or functional meaning, of any mutation in the largest family of proteins in nature. Furthermore, this structure also provides the best characterization of the “trigger” mechanism - the binding of ATP to the kinase and to the oncogenic kinases.

1ATP structure provides us with a picture of the “gun ready to send the signal onto the oncogenic target”. This singular event serves as the triggering mechanism (the Inception) of cancer. CML has been transformed into a chronic, manageable disease as a result of the characterization of the source of the oncogenic signal - ABL.

It is important to realize that without that first structure, the dream of developing specific inhibitors to compete with the ATP “trigger” would be utter nonsense. The structure has spawned the strategy.

DNA-SEQ’s library of over 2,000 highly selected structures contains over 30 million XYZ coordinates. This library serves as testimony to the unprecedented worldwide tour de force of crystallography following the identification of that first structure. To date 16 drugs have received FDA approval and over 200 molecules are in clinical trials to test their veracity in competing with (inhibiting) the trigger mechanism of ATP.

This comprehensive library has been assembled in conjunction with our Alliance Partner, XTAL BioStructures, whose highly sophisticated crystallography expertise is also sought after by many pharmaceutical companies.

The major design criteria of the library was to enable us to align the structures with the trigger (the PKA with bound ATP), and to provide the full complement of critical metals and bound substrates. All other structures can than be aligned to that trigger. The alignment process is highly proprietary in that it involves numerous alterations (pruning) but it remains based on the first crystal structure - PKA.

The Intervention is accomplished by matching the crystal structure of inhibitor complexes to the activating mutation. And finally the Inhibition is accomplished by utilizing the crystal structure to match the inhibitor complexes with common resistance mutations.

DNA-SEQ’s Kinase Crystal Library is the organizing principle of the Alliance pipeline’s data gathering cycles. The data extracted from a patient’s DNA can then be modeled at the San Diego Super Computing Center and provided to the oncologist for a three dimensional visualization of the mutation.

With the modeling completed the search begins. Our crystal based “gene panels” provide precision screening for actionable genes based on crystallographic evidence. This is the critical step in which irrelevant mutants are discarded and a short list of structure based gene selection can be provided to the oncologist to determine their patients’ treatment plan.

Ultimately, DNA-SEQ’s Kinase Crystal Library will provide the aligned inhibitors for the quantum search algorithm being developed with D-Wave to more precisely match a molecule to a mutation. Efficacy is everything.