7ama

<table><tr><td colspan='2'>[[7ama]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AMA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMA FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RMK:~{N}-[(2~{S})-1,1-dicyclopropyl-3-[[4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)phenyl]amino]-3-oxidanylidene-propan-2-yl]-2-propan-2-yl-pyrazole-3-carboxamide'>RMK</scene></td></tr>

== Function ==

[[https://www.uniprot.org/uniprot/IL17_HUMAN IL17_HUMAN]] Induces stromal cells to produce proinflammatory and hematopoietic cytokines. Enhances the surface expression of ICAM1/intracellular adhesion molecule 1 in fibroblasts.

<div style="background-color:#fffaf0;">

== Publication Abstract from PubMed ==

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

 

<div class="pdbe-citations 7ama" style="background-color:#fffaf0;"></div>

== References ==

[[Category: Andrews, M D]]

[[Category: Dack, K N]]

[[Category: Groot, M J.de]]

[[Category: Hakansson, M]]

[[Category: Kimbung, R]]

[[Category: Lambert, M]]

[[Category: Logan, D]]

[[Category: Walse, U B]]

[[Category: Immune system]]

[[Category: Interleukin il-17a inhibitor receptor]]