Summary for 8RX9
| Entry DOI | 10.2210/pdb8rx9/pdb |
| Related | 8RX7 |
| Descriptor | Leukotriene A-4 hydrolase, ZINC ION, ACETATE ION, ... (7 entities in total) |
| Functional Keywords | lta4h, inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 70577.14 |
| Authors | Srinivas, H. (deposition date: 2024-02-06, release date: 2024-03-20, Last modification date: 2024-04-10) |
| Primary citation | Thoma, G.,Miltz, W.,Srinivas, H.,Penno, C.A.,Kiffe, M.,Gajewska, M.,Klein, K.,Evans, A.,Beerli, C.,Rohn, T.A. Structure-Guided Elaboration of a Fragment-Like Hit into an Orally Efficacious Leukotriene A4 Hydrolase Inhibitor. J.Med.Chem., 67:5093-5108, 2024 Cited by PubMed Abstract: Leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB). Preclinical studies have provided strong evidence that LTA4H is an attractive drug target for the treatment of chronic inflammatory diseases. Here, we describe the transformation of compound , a fragment-like hit, into the potent inhibitor of LTA4H . Our strategy involved two key steps. First, we aimed to increase the polarity of fragment to improve its drug-likeness, particularly its solubility, while preserving both its promising potency and low molecular weight. Second, we utilized structural information and incorporated a basic amino function, which allowed for the formation of an essential hydrogen bond with Q136 of LTA4H and consequently enhanced the potency. Compound exhibited exceptional selectivity and showed oral efficacy in a KRN passive serum-induced arthritis model in mice. The anticipated human dose to achieve 90% target engagement at the trough concentration was determined to be 40 mg administered once daily. PubMed: 38476002DOI: 10.1021/acs.jmedchem.4c00290 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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