Technology based on unique DNA SEQ XYZ geometry of kinome
DNA SEQ’s “DxRx” platform of A/I driven kinase technology is encapsulated in our patent estate, as designed by our IP Attorney, Dr Lisa Haile. Our patent estate consists of U.S. Patent #10,093,982 and U.S. Patent #10,392,669, and is associated with the initial “know how” of DNA SEQ’s Founder, Janusz Maria Sowadski, which has been derived from the original discovery of the first structure of a protein kinase – cAMP dependent protein kinase catalytic subunit.
The Priority Dates associated with DNA SEQ’s Patent Estate are dated January 27, 2014 for U.S. Patent #10,093,982 and November 18, 2018 for U.S. Patent #10,392,669. We used the original nomenclature as has been initially published in several key publications. The only additional nomenclature referenced is the “Rosetta Stone”, which is used in DNA SEQ’s patented kinome origin, which functions much like a “GPS system” for the crystal kinome in three-dimensional space. It provides a navigatable system for diagnostic prediction and for the drug design of novel inhibitors. It requires only the key to the coordinates of origin of the “DNA-SEQ XYZ geometry” of the kinome.
The core of our patent estate is the A/I driven platform. The key function of the platform is to translate cancer patient genetic response to kinase inhibitors data, into the “DNA SEQ origin of kinome crystal space”. The process of the A/I driven translation begins with imatinib, or Gleevec®, and will expand into other drugs and indications – specifically to other oncogenes with different activating mechanisms. Gleevec®was developed by NOVARTIS with initial collaborative input from the first structure (PKA), which is referred to as the “Rosetta Stone”.
Our developments are described in detail in five sections, which incorporate the translation of cancer patients’ clinical responses from our database, into our crystal structures library, wherein our pattern-matching algorithm and machine-learning capabilities are embedded. DNA SEQ’s technology consists of interlocking technologies that form a fully integrated a DxRx platform, which enables DNA SEQ’s novel diagnostic prediction of an optimal treatment, and DNA SEQ’s precise three-dimensional templates for our drug discovery program.
Part one describes the internal geometry of the roto-translation movement of PKA domains during the binding of ATP and the release of ADP. Two positions, or states, of the domains, are defined wherein the DFG control of the movement is turned off as the phosphate on the activation loop is permanently anchored. An inhibitor protein must be present to turn the kinase activity off.
Part two describes the internal geometry of the roto-translational movement during signaling and how that movement is controlled by the DFG pattern. Using 2138 crystal structures, the internal XYZ kinome geometry, and machine learning we have derived the function, which describes the “dynamics” of the DFG pattern. Utilizing that function, we have identified 508 structures with the DFG INTER conformation.(Patent #10,093,982 and U.S. Patent #10,392,669)
Part three describes the synchronization of the entry of ATP and the target protein. Our machine learning derived function for our analysis of the “dynamic” motion of the DFG controlling the ATP’s entry also provides the key for synchronizing the DFG motion with the dynamics of the activation loop. The activation loop is the entry point for the target protein. The bound chemical “fragments” (including ATP) to the DFG INTER results in shortening one of the axes (Y axis) of the XYZ geometry of the kinome.
Part four describes our process of “translating” treated cancer patients’ genetic clinical responses into the XYZ kinome geometry of the motion of the DFG control and the control of the entry of the target protein. We have identified, in three-dimensional space, several amino acid patterns within the ATP binding cleft. These amino acids are characterized by extremely high amino acid variability among many kinases. Within this region, we have identified “two pivots” on the Y axis of the XYZ geometry of the kinome. At the one of the pivot points that govern the roto-translational movement, many cancer patients, that have been treated with different drugs for different indications, have developed a drug resistance mutation. This finding enables us to provide a highly precise predictive tool for this diversity region, which frequently leads to drug resistance to kinase inhibitors that have been designed to identify the “specificity pockets” within the ATP binding cleft.
Part five describes the practical application of our platform in the case of one specific oncogene. In this oncogene as we have shown that both classes of inhibitors, DFG IN and DFG OUT, are missing the real target, which is the DFG INTER which has very different “specificity” since the DFG dynamics of the two domains can create a myriad of “packets” of specificity. “Specificity pockets” of the DFG IN are different than “specificity pockets” of the DFG OUT, and are therefore different than the “specificity pockets” of DFG INTER. In this oncogene, the DFG INTER (and activation loop INTER position), the bound ATP derivative, which has no ability to transfer phosphate, is positioning its gamma phosphate precisely onto the in-line position for attack into the incoming target protein. Drugs binding to either the DFG IN or DFG OUT invoke drug resistance for a spectrum of cancer patient mutations that mimic the high diversity region of this oncogene – including the Y pivot of the XYZ kinome geometry. Our analysis was done for one specific cancer activation mechanism. Each oncogene, with a different activation mechanism has to be analyzed. To enhance and accelerate this broad analysis, DNA SEQ has developed two highly precise tools that enable predictive diagnostics for the drug resistance mutation profile, and a novel template targeting the DFG INTER conformation.\
- PART ONE: INTERNAL GEOMETRY OF KINOME
- PART THREE: MACHINE LEARNING ALGORITHM REVEALS THE MECHANISM OF ENTRY FOR ATP AND THE TARGET PROTEIN
- PART FOUR: EVOLUTION OF KINOME ATP BINDING CLEFT AND DRUG RESISTANCE
- PART FIVE: PIPELINE OF ACTIVATED ONCOGENES