Drugging the'undruggable'cancer targets
The term'undruggable'was coined to describe proteins that could not be targeted
pharmacologically. However, progress is being made to'drug'many of these targets, and …
pharmacologically. However, progress is being made to'drug'many of these targets, and …
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
JML Ostrem, KM Shokat - Nature reviews Drug discovery, 2016 - nature.com
KRAS is the most frequently mutated oncogene in human cancer. In addition to holding this
distinction, unsuccessful attempts to target this protein have led to the characterization of …
distinction, unsuccessful attempts to target this protein have led to the characterization of …
The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling
AC Dar, KM Shokat - Annual review of biochemistry, 2011 - annualreviews.org
Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic
output. Over time, chemical discovery efforts for kinases have produced ATP-competitive …
output. Over time, chemical discovery efforts for kinases have produced ATP-competitive …
Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2
ME Feldman, B Apsel, A Uotila, R Loewith… - PLoS …, 2009 - journals.plos.org
The mammalian target of rapamycin (mTOR) regulates cell growth and survival by
integrating nutrient and hormonal signals. These signaling functions are distributed between …
integrating nutrient and hormonal signals. These signaling functions are distributed between …
Inhibitor hijacking of Akt activation
T Okuzumi, D Fiedler, C Zhang, DC Gray… - Nature chemical …, 2009 - nature.com
The kinase Akt plays a central role as a regulator of multiple growth factor input signals, thus
making it an attractive anticancer drug target. A-443654 is an ATP-competitive Akt inhibitor …
making it an attractive anticancer drug target. A-443654 is an ATP-competitive Akt inhibitor …
[HTML][HTML] A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling
Summary Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug
targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an …
targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an …
A chemical switch for inhibitor-sensitive alleles of any protein kinase
AC Bishop, JA Ubersax, DT Petsch, DP Matheos… - nature, 2000 - nature.com
Protein kinases have proved to be largely resistant to the design of highly specific inhibitors,
even with the aid of combinatorial chemistry. The lack of these reagents has complicated …
even with the aid of combinatorial chemistry. The lack of these reagents has complicated …
K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions
Somatic mutations in the small GTPase K-Ras are the most common activating lesions found
in human cancer, and are generally associated with poor response to standard therapies …
in human cancer, and are generally associated with poor response to standard therapies …
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
Tumours with mutant BRAF are dependent on the RAF–MEK–ERK signalling pathway for
their growth,,. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells …
their growth,,. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells …
Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3
NV Sergina, M Rausch, D Wang, J Blair, B Hann… - Nature, 2007 - nature.com
Oncogenic tyrosine kinases have proved to be promising targets for the development of
highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the …
highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the …