Kevan M. Shokat
Co-invented ATP-competitive "TORKinib" mTOR inhibitors that block both mTORC1 and mTORC2
BA, Reed College · PhD, UC Berkeley (Peter G. Schultz lab) · postdoc, Stanford University (Christopher Goodnow lab) · faculty, Princeton University · now Professor of Cellular and Molecular Pharmacology, UC San Francisco, joint appointment in Chemistry at UC Berkeley, and HHMI Investigator (since 2005)
Rapamycin is an allosteric mTORC1 inhibitor: it only partly suppresses the complex and doesn't touch mTORC2 at all, so cap-dependent translation driven by 4E-BP1 phosphorylation often survives treatment. In 2009, Shokat's group solved this by building small molecules that instead plug directly into mTOR's ATP-binding pocket — the kinase's active site, shared by both mTORC1 and mTORC2. These "TORKinibs" (PP242, PP30) shut down both complexes at once and, unlike rapamycin, fully collapse cap-dependent translation. Christopher Thoreen and David Sabatini's lab reached the same conclusion independently and simultaneously with their inhibitor Torin1 — together the two papers defined an entire new class of mTOR drugs built on chemistry rather than the natural product rapamycin.
Shokat trained as a chemist, earning his PhD at Berkeley with Peter Schultz working on catalytic antibodies, then moved into biology as a postdoc with immunologist Christopher Goodnow at Stanford, studying tyrosine kinases in B-cell tolerance. His own Princeton lab pioneered 'bump-and-hole' engineering — mutating a kinase's ATP pocket and pairing it with a matched, cell-permeable ATP analog so that one specific kinase, out of hundreds in the genome, can be selectively inhibited or traced to its direct substrates.
That chemical toolkit later turned toward oncogenic signaling: in 2013 his lab published the first covalent inhibitors of KRAS G12C, exploiting a cysteine created by the mutation to lock the oncoprotein in its inactive, GDP-bound state — turning a target long dismissed as 'undruggable' into the basis for an entire clinical drug class (sotorasib, adagrasib, and successors). He is a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences, and continues to run an active chemical biology lab at UCSF alongside his HHMI investigatorship.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 Introduces ATP-competitive mTOR kinase inhibitors (PP242, PP30) that hit both mTORC1 and mTORC2, shutting down the cap-dependent translation that rapamycin leaves intact. |
| 2016 | M | Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor ROD2016 Introduces RapaLink-1, a bivalent third-generation mTOR inhibitor that overcomes resistance mutations that defeat both rapalogs and first-generation TORKinibs. |