4EHG
B-Raf Kinase Domain in Complex with an Aminopyridimine-based Inhibitor
Summary for 4EHG
| Entry DOI | 10.2210/pdb4ehg/pdb |
| Related | 4EHE |
| Descriptor | Serine/threonine-protein kinase B-raf, N-{2,4-difluoro-3-[({6-[(2-hydroxyethyl)amino]pyrimidin-4-yl}carbamoyl)amino]phenyl}propane-1-sulfonamide (2 entities in total) |
| Functional Keywords | kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (By similarity): P15056 |
| Total number of polymer chains | 2 |
| Total formula weight | 71356.09 |
| Authors | Voegtli, W.C. (deposition date: 2012-04-02, release date: 2013-04-24, Last modification date: 2024-02-28) |
| Primary citation | Mathieu, S.,Gradl, S.N.,Ren, L.,Wen, Z.,Aliagas, I.,Gunzner-Toste, J.,Lee, W.,Pulk, R.,Zhao, G.,Alicke, B.,Boggs, J.W.,Buckmelter, A.J.,Choo, E.F.,Dinkel, V.,Gloor, S.L.,Gould, S.E.,Hansen, J.D.,Hastings, G.,Hatzivassiliou, G.,Laird, E.R.,Moreno, D.,Ran, Y.,Voegtli, W.C.,Wenglowsky, S.,Grina, J.,Rudolph, J. Potent and selective aminopyrimidine-based B-raf inhibitors with favorable physicochemical and pharmacokinetic properties. J.Med.Chem., 55:2869-2881, 2012 Cited by PubMed Abstract: Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described. PubMed: 22335519DOI: 10.1021/jm300016v PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
Download full validation report
