ACS Medicinal Chemistry Letters
Letter
Dennis H. Leung − Small Molecule Pharmaceutical Sciences,
Genentech, Inc., South San Francisco, California 94080,
United States
(oral); RAF, rapidly accelerated fibrosarcoma; SPRY4, sprouty
RTK signaling antagonist 4; TPSA, topological polar surface
area; Vdss, volume of distribution
Wendy Liu − Discovery Chemistry, Genentech, Inc., South San
Francisco, California 94080, United States
REFERENCES
■
Shiva Malek − Molecular Oncology, Genentech, Inc., South
San Francisco, California 94080, United States
Mark Merchant − Translational Oncology, Genentech, Inc.,
South San Francisco, California 94080, United States
John G. Moffat − Biochemical and Cellular Pharmacology,
Genentech, Inc., South San Francisco, California 94080,
United States
Christine S. Muli − Small Molecule Pharmaceutical Sciences,
Genentech, Inc., South San Francisco, California 94080,
United States
Christine J. Orr − Translational Oncology, Genentech, Inc.,
South San Francisco, California 94080, United States
Brendan T. Parr − Discovery Chemistry, Genentech, Inc.,
South San Francisco, California 94080, United States
Frances Shanahan − Molecular Oncology, Genentech, Inc.,
South San Francisco, California 94080, United States
Christopher J. Sneeringer − Biochemical and Cellular
Pharmacology, Genentech, Inc., South San Francisco,
California 94080, United States
(1) Cox, A. D.; Fesik, S. W.; Kimmelman, A. C.; Luo, J.; Der, C. J.
Discovery 2014, 13, 828−851.
(2) Moore, A. R.; Rosenberg, S. C.; McCormick, F.; Malek, S. RAS-
Discovery 2020, 19, 533−552.
(3) Hatzivassiliou, G.; Song, K.; Yen, I.; Brandhuber, B. J.; Anderson,
D. J.; Alvarado, R.; Ludlam, M. J. C.; Stokoe, D.; Gloor, S. L.; Vigers,
G.; Morales, T.; Aliagas, I.; Liu, B.; Sideris, S.; Hoeflich, K. P.; Jaiswal,
B. S.; Seshagiri, S.; Koeppen, H.; Belvin, M.; Friedman, L. S.; Malek,
(4) Dougherty, M. K.; Muller, J.; Ritt, D. A.; Zhou, M.; Zhou, X. Z.;
̈
Copeland, T. D.; Conrads, T. P.; Veenstra, T. D.; Lu, K. P.; Morrison,
Cell 2005, 17, 215−224.
(5) Yen, I.; Shanahan, F.; Merchant, M.; Orr, C.; Hunsaker, T.;
Durk, M.; La, H.; Zhang, X.; Martin, S. E.; Lin, E.; Chan, J.; Yu, Y.;
Amin, D.; Neve, R. M.; Gustafson, A.; Venkatanarayan, A.; Foster, S.
Tumors. Cancer Cell 2018, 34, 611−625.
Weiru Wang − Structural Biology, Genentech, Inc., South San
Francisco, California 94080, United States
Ivana Yen − Molecular Oncology, Genentech, Inc., South San
Francisco, California 94080, United States
Jianping Yin − Structural Biology, Genentech, Inc., South San
Francisco, California 94080, United States
(6) Huestis, M. P.; Dela Cruz, D.; DiPasquale, A. G.; Durk, M. R.;
Eigenbrot, C.; Gibbons, P.; Gobbi, A.; Hunsaker, T. L.; La, H.; Leung,
D. H.; Liu, W.; Malek, S.; Merchant, M.; Moffat, J. G.; Muli, C. S.;
Orr, C. J.; Parr, B. T.; Shanahan, F.; Sneeringer, C. J.; Wang, W.; Yen,
3940−3955.
Complete contact information is available at:
Notes
(7) (a) Henry, J. R.; Kaufman, M. D.; Peng, S.-B.; Ahn, Y. M.;
Caldwell, T. M.; Vogeti, L.; Telikepalli, H.; Lu, W.-P.; Hood, M. M.;
Rutkoski, T. J.; Smith, B. D.; Vogeti, S.; Miller, D.; Wise, S. C.; Chun,
L.; Zhang, X.; Zhang, Y.; Kays, L.; Hipskind, P. A.; Wrobleski, A. D.;
Lobb, K. L.; Clay, J. M.; Cohen, J. D.; Walgren, J. L.; McCann, D.;
Patel, P.; Clawson, D. K.; Guo, S.; Manglicmot, D.; Groshong, C.;
4179. (b) Peng, S.-B.; Henry, J. R.; Kaufman, M. D.; Lu, W.-P.; Smith,
B. D.; Vogeti, S.; Rutkoski, T. J.; Wise, S.; Chun, L.; Zhang, Y.; Van
Horn, R. D.; Yin, T.; Zhang, X.; Yadav, V.; Chen, S.-H.; Gong, X.; Ma,
X.; Webster, Y.; Buchanan, S.; Mochalkin, I.; Huber, L.; Kays, L.;
Donoho, G. P.; Walgren, J.; McCann, D.; Patel, P.; Conti, I.;
384−398. (c) Chen, S.-H.; Gong, X.; Zhang, Y.; Van Horn, R. D.; Yin,
T.; Huber, L.; Burke, T. F.; Manro, J.; Iversen, P. W.; Wu, W.;
Bhagwat, S. V.; Beckmann, R. P.; Tiu, R. V.; Buchanan, S. G.; Peng,
821−832.
The authors declare the following competing financial
interest(s): All authors are employees/former employees of
Genentech, Inc. and may hold stock in Roche Holding AG. All
studies were funded by Genentech, Inc.
Coordinates and structure factors for the BRAF domain
complex are available in the PDB with accession code 6XLO
(7). The authors will release the atomic coordinates and
experimental data upon article publication.
ACKNOWLEDGMENTS
■
M.P.H. thanks Kim Huard for support and encouragement.
Kinase selectivity data courtesy of Selectscreen service from
Life Technologies, a Thermo Fisher company, Madison, WI,
USA. We thank staff of Beamline 5.0.2 of the Advanced Light
Source for assistance during data collection.
ABBREVIATIONS USED
■
CL, clearance; DELFIA, dissociation-enhanced lanthanide
fluorescence immunoassay; DFG, Asp-Phe-Gly; DUSP6, dual
specificity phosphatase 6 kinase; ERK, extracellular signal-
regulated kinase; F, bioavailability; HCT, human colorectal
cancer cells; IV, intravenous; KRAS, Kirsten rat sarcoma;
log D, log of distribution coefficient; MDCK, Madin−Darby
canine kidney cell; MEK, mitogen-activated protein kinase
kinase; MAPK, mitogen-activated protein kinase; MCT,
methylcellulose-tween; MP, melting point; MS, mass spec-
trometry; Papp, permeability coefficient; PK, pharmacokinetic;
PKPD, pharmacokinetic/pharmacodynamics; PO, per os
(8) Example of N-methyl polarized CH protein interactions: Hanan,
E. J.; van Abbema, A.; Barrett, K.; Blair, W. S.; Blaney, J.; Chang, C.;
Eigenbrot, C.; Flynn, S.; Gibbons, P.; Hurley, C. A.; Kenny, J. R.;
Kulagowski, J.; Lee, L.; Magnuson, S. M.; Morris, C.; Murray, J.;
Pastor, R. M.; Rawson, T.; Siu, M.; Ultsch, M.; Zhou, A.; Sampath,
796
ACS Med. Chem. Lett. 2021, 12, 791−797