The activity of many proteins is controlled through phosphorylation by kinases and dephosphorylation by phosphatases. Overactive kinases are one of the major drivers of tumors and, as a result, kinase inhibitors are a mainstay of oncology drug development.
But “activation of the brakes, the phosphatases, could be equally therapeutically viable for the treatment of a broad range of cancers” to kinase inhibition, Goutham Narla told the audience at the 2020 American Association for Cancer Research (AACR) meeting.
Overall, phosphatases have been less well explored than kinases, and most targeting has been in the form of inhibitors, which tend to be easier to develop than activators.
Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) inhibitors, for example, are being developed for the treatment of KRAS-driven cancers. At a session on “Advances in Cancer Drug Design and Discovery,” Astex Pharmaceuticals Inc.’s Christopher Johnson gave an overview of using fragment-based drug design to identify SHP2 inhibitors.
Narla is division chief of genetic medicine at the University of Michigan and scientific founder of Rappta Therapeutics Inc., a startup devoted to the development of activators for a family of phosphatases that collectively go by the name protein phosphatase 2A (PP2A).
PP2A phosphatases consist of a scaffold subunit that binds a catalytic subunit, and one of 20 different regulatory subunits that account for what Narla called the “extraordinary substrate diversity” of PP2As, which collectively have a hand in more than half of all cellular dephosphorylation events.
Given its outsize role in cellular dephosphorylation, it is not surprising that PP2A is also deregulated in many different pathological processes. And if phosphatases as a whole are undertargeted, PP2A has gotten relatively generous attention from biopharma.
However, Narla said, his team has developed direct binders of a specific form of PP2A that he argues differentiates them from the pack.
In his talk, he described an activator, DT-061, that stabilizes PP2A by binding enzymes that contain the regulatory subunit B56-a.
DT-061 is highly specific to that particular regulatory subunit, Narla explained, because “closely related family members…. have a lysine at the 256 position” that forms a salt bridge and keeps DT-061 from binding in a pocket that is open in the B56-a subunit, which has the amino acid threonine in position 256.
When DT-061 binds, it exerts a stabilizing effect on the phosphatase that increases its activity. The B56-a containing subunit has the transcription factor Myc as one of its targets and, in animal models, treatment with the inhibitor was able to block the growth of Myc-driven cancers, including triple-negative breast cancer and Burkitt’s lymphoma. A genetically engineered version of Myc that was impervious to PP2A was not affected by DT-061.
The team published those results, which were obtained in collaboration with researchers at Case Western Reserve University, in the April 20, 2020, issue of Cell. In his talk at AACR, Narla also described screening studies in which his team looked for synergistic relationships that could suggest combination partners.
Those studies suggested that a PP2A activator would be synergistic with MEK inhibitors. MEK is a downstream member of the pathway that begins with Ras/Raf. FDA-approved MEK inhibitors include Mekinist (trametinib, Novartis AG) Mektovi (binimetinib, Array Biopharma), Cotellic (cobimetinib, Roche Holding AG) and, as of April 10, Koselugo (selumetinib, Astrazeneca plc/Merck & Co. Inc.).