Revolution Medicines is pursuing discovery and development of protein tyrosine phosphatase (PTP) inhibitors. The proven utility of tyrosine kinase inhibitors in treating certain forms of cancer has established modulation of tyrosine phosphorylation as a powerful therapeutic strategy. PTPs function as counter-regulatory players with tyrosine kinases to achieve and maintain signaling homeostasis, and to date these proteins have represented a largely untapped target class.
The PTP SHP2 (PTPN11) is a known oncogenic driver in a subset of hematologic cancers, and also a central signaling node in diverse regulatory pathways (Figure A) - such as the RTK-Ras-MAPK cascade – that are often dysregulated in a wide variety of solid and liquid tumors. Inhibition of SHP2 can effectively block these signaling cascades and, in preclinical experimental settings, abrogates tumor growth. We believe that a potent, selective and orally-bioavailable inhibitor of SHP2 represents a valid therapeutic option for treatment of cancers that rely on pathways that depend on SHP2.
In addition, SHP2 has been proposed to be an important intracellular mediator of inhibitory signals transmitted by one or more immune checkpoint receptors, such as the PD-1/PD-L1 axis, that can attenuate anti-tumor immune responses. Inhibition of SHP2 function may be an approach to augmenting or substituting for other modalities to block immune checkpoints.
REVOLUTION Medicines currently is in lead optimization on a novel collection of inhibitors of this frontier cancer target.
Aberrant activation of the PI3K- AKT-PTEN-mTOR signaling pathway occurs in the majority of cancers. The mTOR Complex 1 (mTORC1) acts as a central node in the pathway through the positive regulation of translation of key oncogenes (Figure B) . Phosphorylation of the translation regulator 4EBP1 is induced when mTORC1 signaling is triggered in cancer cells. Since 4EBP1 is a tumor suppressor, its inactivation by phosphorylation is believed to be an oncogenic contributor. This leads to the hypothesis that preservation of 4EBP1 tumor suppressor activity should confer significant therapeutic value in specific cancer contexts. The natural product rapamycin partially inhibits mTORC1 activity, and derivatives of rapamycin (rapalogs) are used to treat some forms of cancer. However, rapalogs do not potently and consistently inhibit mTORC1-mediated phosphorylation of 4EBP1 in cancer cells. Thus far, efforts by the field to develop active site inhibitors of the mTOR kinase have failed to achieve the goal of preserving 4EBP1 tumor suppressor function in patients because concurrent inhibition of the mTORC2 complex confers a poor tolerability profile.
Through its proprietary synthetic chemistry platform, REVOLUTION Medicines is developing a novel class of inhibitors that preserve the tumor suppressor function of 4EBP1 by thoroughly yet selectively inhibiting mTORC1.
The company’s SHP2 program, 4EBP1 program, additional targets, and the product engine broadly represent corporate partnership opportunities. Please contact us at BD@revolutionmedicines.com for more information.