1258298-00-8Relevant articles and documents
Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation
Hanan, Emily J.,Eigenbrot, Charles,Bryan, Marian C.,Burdick, Daniel J.,Chan, Bryan K.,Chen, Yuan,Dotson, Jennafer,Heald, Robert A.,Jackson, Philip S.,La, Hank,Lainchbury, Michael D.,Malek, Shiva,Purkey, Hans E.,Schaefer, Gabriele,Schmidt, Stephen,Seward, Eileen M.,Sideris, Steve,Tam, Christine,Wang, Shumei,Yeap, Siew Kuen,Yen, Ivana,Yin, Jianping,Yu, Christine,Zilberleyb, Inna,Heffron, Timothy P.
supporting information, p. 10176 - 10191 (2015/01/16)
Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.
Lead identification of novel and selective TYK2 inhibitors
Liang, Jun,Tsui, Vickie,Van Abbema, Anne,Bao, Liang,Barrett, Kathy,Beresini, Maureen,Berezhkovskiy, Leo,Blair, Wade S.,Chang, Christine,Driscoll, James,Eigenbrot, Charles,Ghilardi, Nico,Gibbons, Paul,Halladay, Jason,Johnson, Adam,Bir Kohli, Pawan,Lai, Yingjie,Liimatta, Marya,Mantik, Priscilla,Menghrajani, Kapil,Murray, Jeremy,Sambrone, Amy,Xiao, Yisong,Shia, Steven,Shin, Young,Smith, Jan,Sohn, Sue,Stanley, Mark,Ultsch, Mark,Zhang, Birong,Wu, Lawren C.,Magnuson, Steven
, p. 175 - 187 (2013/10/01)
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.
