The problem with resistance

THE POINT OF ORIGIN

In 1991, at the University of California in San Diego, a group of scientists led by Janusz M. Sowadski discovered the first crystal structure of a protein kinase – catalytic subunit of cAMP dependent protein kinase. This discovery provided the foundation for a new chapter of targeted oncology drug development. Now over 35 FDA approved kinase inhibitors constitute a $40B+ annual market, which has provided enormous relief to cancer patients. The crystal structure of the catalytic subunit of this protein kinase (PKA), often referred to as “the Rosetta Stone”, provided a structural paradigm for the entire kinome, This pivotal discovery proved particularly significant due to the fact that the family of 500+ human kinases serves as key regulators of the communication within the cell, as well as between the cells and their environment. This family is also a major oncogenic family, and mutations, within many members of this family, can lead to a myriad of human cancers.

In 1993, in collaboration with Ciba-Geigy, now Novartis AG Basel, a group of Ciba-Geigy scientists, including Janusz M. Sowadski, used the crystal structure of PKA as a three dimensional template to design the first 3D model of Ciba inhibitors bound to PKA. Using homology modeling and a simple pattern matching methodology the group identified the unexpected CIBA inhibitors’ specificity, which was located in a common ATP cleft in a number of kinases. This led to the development of specific ATP competitive inhibitors, most notably Novartis’ Gleevec®, which was designed for the treatment of chronic myelogenous leukemia (CML). This template of the ATP site with its subtle diversity, discovered by Dr. Sowadski, served as both the catalyst and the structural basis for developing many approved kinase inhibitors.  ATP competitive inhibitors, most notably Novartis’ Gleevec®, which was designed for the treatment of chronic myelogenous leukemia (CML).

The impressive development of kinase inhibitors, along with the resulting response data gathered from cancer patients, over time, has taught us two significant lessons:

  • Kinase inhibitors have proven to provide an optimal treatment methodology for a specific subgroup of patients with kinase activation mutations​
  • However, following a significant period of positive response, the patients are overwhelmed by drug resistance.

In 2013, Janusz M. Sowadski formed DNA SEQ to search for a deeper understanding of cancers’ resistance. His approach was to assemble a team to attempt to integrate emerging technologies in a manner that could more precisely explore the structural pattern-matching concept that began in 1993. His intent was to discover what may have been overlooked in his original discovery that could be a design flaw in all subsequent kinase inhibitors built on that discovery. The first aspect of DNA SEQ’s mission is to identify those kinases with “broken control” and to selectively take them out of action. The second aspect is to make sure that a cancer impaired kinase does not resist drug treatment.

The Alliance grew out of Janusz’s introduction to Eric Ladizinsky and David Doyle. Eric is the CSO of D Wave Quantum Systems, and he believed that due to the structural aspects of crystallography, their AI team could integrate a pattern matching algorithm. David is a serial entrepreneur who believed that with a world class advisory team and technology partners, he could find the seed capital.

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