7PPI

Crystal STRUCTURE OF NAMPT IN COMPLEX WITH Compound 11

7PPI の概要

• エントリーDOI: 10.2210/pdb7ppi/pdb
• 分子名称: Nicotinamide phosphoribosyltransferase, N-[4-[(5R)-1-(4-azanylbutyl)-6-oxidanylidene-5-quinolin-5-yl-4,5-dihydropyridazin-3-yl]phenyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide, PHOSPHATE ION, ... (6 entities in total)
• 機能のキーワード: small molecule inhibitor, nmprtase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 225646.79

構造登録者

Hillig, R.C. (登録日: 2021-09-13, 公開日: 2022-06-15, 最終更新日: 2024-01-31)

主引用文献

Bohnke, N.,Berger, M.,Griebenow, N.,Rottmann, A.,Erkelenz, M.,Hammer, S.,Berndt, S.,Gunther, J.,Wengner, A.M.,Stelte-Ludwig, B.,Mahlert, C.,Greven, S.,Dietz, L.,Jorissen, H.,Barak, N.,Bomer, U.,Hillig, R.C.,Eberspaecher, U.,Weiske, J.,Giese, A.,Mumberg, D.,Nising, C.F.,Weinmann, H.,Sommer, A.
A Novel NAMPT Inhibitor-Based Antibody-Drug Conjugate Payload Class for Cancer Therapy.
Bioconjug.Chem., 33:1210-1221, 2022

PubMed Abstract: Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a new mode of action for cancer-targeting antibody-drug conjugates (ADCs) with activity also in slowly proliferating cells. To extend the repertoire of available effector chemistries, we have developed a novel structural class of NAMPT inhibitors as ADC payloads. A structure-activity relationship-driven approach supported by protein structural information was pursued to identify a suitable attachment point for the linker to connect the NAMPT inhibitor with the antibody. Optimization of scaffolds and linker structures led to highly potent effector chemistries which were conjugated to antibodies targeting C4.4a (LYPD3), HER2 (c-erbB2), or B7H3 (CD276) and tested on antigen-positive and -negative cancer cell lines. Pharmacokinetic studies, including metabolite profiling, were performed to optimize the stability and selectivity of the ADCs and to evaluate potential bystander effects. Optimized NAMPTi-ADCs demonstrated potent antitumor efficacy in target antigen-expressing xenograft mouse models. This led to the development of highly potent NAMPT inhibitor ADCs with a very good selectivity profile compared with the corresponding isotype control ADCs. Moreover, we demonstrate─to our knowledge for the first time─the generation of NAMPTi payload metabolites from the NAMPTi-ADCs and . In conclusion, NAMPTi-ADCs represent an attractive new payload class designed for use in ADCs for the treatment of solid and hematological cancers.

PubMed: 35658441
DOI: 10.1021/acs.bioconjchem.2c00178

実験手法

X-RAY DIFFRACTION (2.33 Å)