Kevan M. Shokat
Co-developed the ATP-competitive 'TORKinib' mTOR inhibitors that block both mTORC1 and mTORC2, and later, with Neal Rosen's lab at Memorial Sloan Kettering, RapaLink-1, a third-generation inhibitor that overcomes mTOR resistance mutations
Professor of Cellular and Molecular Pharmacology, UC San Francisco, joint appointment in Chemistry at UC Berkeley, and HHMI Investigator (since 2005) · faculty, Princeton University · postdoc, Stanford University (Christopher Goodnow lab) · PhD, UC Berkeley (Peter G. Schultz lab) · BA, Reed College
Faculty profile, UCSF (San Francisco, California, USA) ↗ Lab lineagetrained under Christopher C. Goodnow →
Portrait: Howard Hughes Medical Institute
Rapamycin is an allosteric mTORC1 inhibitor: it only partly suppresses the complex and does not acutely inhibit mTORC2, 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. Carson Thoreen and David Sabatini's lab reached the same conclusion independently and simultaneously with their inhibitor Torin1 — together with other 2009 reports (such as Ku-0063794 and WYE-354), these 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
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| 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. |
| 2010 | M | Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E HSI2010 Genetic dissection shows the 4E-BP1-eIF4E axis mediates oncogenic mTOR signalling and is druggable. |
| 2012 | M | The translational landscape of mTOR signalling steers cancer initiation and metastasis HSI2012 Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result. |
| 2016 | M | Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor ROD2016 With Neal Rosen's lab, introduces RapaLink-1, a bivalent third-generation mTOR inhibitor that overcomes resistance mutations that defeat both first-generation rapalogs and second-generation TORKi. |
Co-authors in the Atlas 11
People with a profile here who share at least one study with Kevan M. Shokat.
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- Davide Ruggero 3 shared studies Showed that oncogenic mTOR signalling reprograms which mRNAs are translated, and that tumours become addicted to this through the 4E-BP–eIF4E axis. His UCSF lab found that mTOR-driven translation of a specific set of mRNAs promotes prostate cancer invasion and metastasis
- Andrew C. Hsieh 2 shared studies Showed, as first author in Davide Ruggero's lab, that oncogenic mTOR drives cancer metastasis by selectively translating a specific pro-invasion mRNA program
- Matthew R. Janes Showed, as first author in David Fruman's lab, that a dual TORC1/2 kinase inhibitor kills leukemia cells with much weaker effects on normal lymphocytes than rapamycin
- Morris E. Feldman Chemical biologist who, in the Shokat lab at UCSF, introduced PP242 and the TORKinib class of drugs that block mTOR's active site and reach the outputs rapamycin misses
- Neal Rosen Showed that blocking mTORC1 releases a feedback brake on receptor tyrosine kinases and AKT, explaining how tumours escape mTOR and PI3K inhibitors and shaping how these drugs are combined in the clinic
- Nicholas T. Ingolia Known for ribosome profiling, a method that reads out which messenger RNAs ribosomes are translating across a whole genome; the study in the Atlas used this approach to map mTOR-controlled translation in prostate cancer.
- Robbie Loewith Showed, as first author in Michael Hall's lab, that yeast TOR exists as two distinct complexes, the basis of the TORC1/TORC2 framework
- Sabina Cosulich Cancer drug discovery scientist at AstraZeneca whose work spans PI3K and mTOR pathway inhibitors, PARP1 inhibitors and phosphoinositide lipid signalling
- Vanessa S. Rodrik-Outmezguine Showed that tumours reactivate AKT after mTOR kinase inhibition, and that the third-generation inhibitor RapaLink-1 overcomes mTOR resistance mutations
- Yi Liu Drug-discovery scientist who builds selective kinase inhibitors, including the active-site mTOR inhibitor INK128
- Zachary A. Knight Neuroscientist whose lab studies the brain mechanisms behind appetite, thirst and body-temperature preference; he is a co-author of the 2009 study that introduced the TORKinibs PP242 and PP30.
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