Revolution Medicines has made a major commitment toward discovering and developing small molecule inhibitors of protein tyrosine phosphatases (PTPs), enzymes that regulate critical cellular proteins by selectively removing phosphate groups attached to certain tyrosine residues.

PTPs function as counter-regulatory players with tyrosine kinases to modulate signal transduction that induces normal or cancer-causing cell growth, differentiation or activation. The proven utility of tyrosine kinase inhibitors in treating some forms of cancer has established modulation of tyrosine phosphorylation as a powerful therapeutic strategy. To date, PTPs have been difficult to inhibit effectively with conventional small molecule drugs and therefore represent a largely untapped target class. For example, effectively inhibiting SHP2 may render a large group of cancer-causing genetic abnormalities "actionable" (that is, amenable to drug treatment) that have hitherto not been easily treatable.


The PTP SHP2 (the tyrosine phosphatase produced by the oncogene PTPN11) is a known oncogenic driver in a subset of cancers, and also a central signaling node in diverse regulatory pathways—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, frequently abrogates tumor growth and/or results in tumor cell death. We believe that a potent, selective and orally bioavailable inhibitor of SHP2 represents a valid therapeutic option for treatment of certain cancers that rely on, or are "addicted" to, abnormalities in signaling pathways that can be regulated or amplified by SHP2. These include major cancers such as lung cancers, colon cancers and melanomas harboring certain mutations in cancer-driving genes such as KRAS, NF1 or BRAF. We have reported new scientific findings by our team in collaboration with Trever Bivona, M.D., Ph.D. and his research group at the University of California, San Francisco that uncovered this potential therapeutic strategy. 

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 antitumor immune responses. Inhibition of SHP2 function may be an approach to augmenting or substituting for other modalities to block immune checkpoints. Some cancers that rely on SHP2-dependent signaling may also be poorly responsive to currently available immune therapies, representing an opportunity for the potential dual action for SHP2 inhibitors.

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Our lead molecule is a potent, selective, orally available inhibitor of SHP2 that is expected to enter clinical trials in patients with advanced cancer in 2018.

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SHP1 (produced by the PTPN6 gene) is a tyrosine phosphatase expressed in blood cells, particularly those of the immune system.

It is activated by signaling through a variety of receptors that negatively regulate various immune cells including T cells, B cells, dendritic cells and macrophages. There is substantial genetic evidence—particularly from the motheaten mouse that has lost expression of SHP1—that SHP1 serves as a global suppressor of activation of the adaptive and innate arms of the immune system. Hence, an inhibitor of SHP1 would be predicted to disinhibit immune responses by operating across these two arms and at their interface. SHP1 inhibition may serve as a therapeutic approach to sensitizing the immune system to cancer neoantigens in order to expand treatment of certain cancers beyond the current boundaries of checkpoint inhibitor therapy. SHP1 is a close relative of SHP2 based on similarities in primary sequence, structure and intramolecular (allosteric) regulation. Leveraging insights we’ve gained through our advanced SHP2 program, we have an active biology and small molecule drug discovery program directed toward this important target on the cutting edge of immuno-oncology.


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