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Some frontier targets are suitable to drug discovery focused on small molecule ligands whose size and physiochemical properties (“Rule of 5” or “Ro5”) are correlated with oral bioavailability, while other targets require larger and more complex ligands (“Beyond Rule of 5” or “bRo5”) that go beyond most traditional drug discovery platforms in pharmaceutical companies.

Many Ro5 targets have been successfully drugged already, and an increasing number of bRo5 targets are emerging that require advanced drug design and synthesis methods. Examples of such targets include multimeric protein complexes with essential protein-protein interfaces that determine functionality. mTORC1 is a very large multimeric protein complex that phosphorylates a variety of critical downstream proteins, including 4EBP1. Thus far Ro5 compounds directed to mTORC1 have proven to be imperfect cancer drugs and none are approved for use. Revolution Medicines has a major commitment to developing bRo5 small molecule drug candidates for targets like 4EBP1/mTORC1.

Aberrant activation of the PI3K-AKT-PTEN-mTOR signaling pathway, which occurs in the majority of cancers, drives the production of cancer-causing proteins.

The mTOR Complex 1 (mTORC1) acts as a central node in the pathway by driving a variety of biological outcomes that promote cancer, including stimulating translation of key oncogenes. When mTORC1 signaling is triggered in cancer cells, it causes phosphorylation and inactivation of the translation inhibitor 4EBP1. Since 4EBP1 is a tumor suppressor, its inactivation by phosphorylation is believed to be an oncogenic contributor. Understanding this pathway leads to the hypothesis that preservation of 4EBP1 tumor suppressor activity should confer significant therapeutic value in specific cancer contexts. Our goal is to develop new compounds that effectively prevent phosphorylation of 4EBP1—and thereby preserve its activity as a tumor suppressor—even when the mTORC1 pathway is activated.

The natural product rapamycin partially inhibits mTORC1 activity, and derivatives of rapamycin (rapalogs) are used to treat some forms of cancer, including breast cancer and renal cell carcinoma. Unfortunately, rapamycin and other known rapalogs do not potently and consistently inhibit mTORC1-mediated phosphorylation of 4EBP1 in cancer cells. In addition, rapamycin and rapalogs have clinical toxicities that may prevent them being administered to patients at doses required to effectively reactivate 4EBP1. Alternative efforts by the drug discovery field to develop active site inhibitors of the mTOR kinase have failed to achieve the goal of preserving 4EBP1 tumor suppressor function in patients due to a poor tolerability profile, which may be attributable at least in part due to concurrent inhibition of the mTORC2 complex (which is also sensitive to rapalogs).

Through its proprietary synthetic chemistry platform, Revolution Medicines is developing a novel class of bRo5 inhibitors that preserve the tumor suppressor function of 4EBP1 by thoroughly yet selectively inhibiting mTORC1 and minimizing or entirely avoiding inhibition of mTORC2 and other cellular enzymes. We hypothesize that by avoiding off-target effects, our proprietary inhibitors will be uniquely suitable for administration to cancer patients at doses that reactivate the tumor suppressor effects of 4EBP1.

We have developed a collection of potent and highly selective drug leads targeting 4EBP1/mTORC1. These compounds are currently undergoing preclinical testing to guide late-stage optimization as needed in order to identify a development candidate that can be brought forward for clinical trials.

 

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