6XIH
Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile
Summary for 6XIH
| Entry DOI | 10.2210/pdb6xih/pdb |
| Related | 5UP3 |
| Descriptor | Mitogen-activated protein kinase kinase kinase 5, (2R)-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}oxane-2-carboxamide (3 entities in total) |
| Functional Keywords | transferase, metal-binding, apoptosis, serine/threonine kinase, metal binding protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 67242.81 |
| Authors | Dougan, D.R. (deposition date: 2020-06-19, release date: 2020-08-12, Last modification date: 2023-10-18) |
| Primary citation | Bigi-Botterill, S.V.,Ivetac, A.,Bradshaw, E.L.,Cole, D.,Dougan, D.R.,Ermolieff, J.,Halkowycz, P.,Johnson, B.,McBride, C.,Pickens, J.,Sabat, M.,Swann, S. Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3character and an exquisite selectivity profile. Bioorg.Med.Chem.Lett., 30:127405-127405, 2020 Cited by PubMed Abstract: Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC = 24 nM and K < 1 nM. Of the 350 kinases tested, 10 has an IC ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. PubMed: 32738982DOI: 10.1016/j.bmcl.2020.127405 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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