View source for 9pw6


==Myeloid cell leukemia-1 (Mcl-1) complexed with compound 8==
<StructureSection load='9pw6' size='340' side='right'caption='[[9pw6]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9pw6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9PW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PW6 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.068&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CL3:7-[(4~{R})-7-chloranyl-10-[3-(4-chloranyl-3,5-dimethyl-phenoxy)propyl]-4-methyl-1-oxidanylidene-6-(1,3,5-trimethylpyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2-yl]-1-(2-methoxyethyl)-5-methyl-indole-2-carboxylic+acid'>A1CL3</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9pw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pw6 OCA], [https://pdbe.org/9pw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pw6 RCSB], [https://www.ebi.ac.uk/pdbsum/9pw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pw6 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a &gt;10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model.,Tarr JC, Jeon K, Veerasamy N, Aichinger M, Salovich JM, Zhao B, Sensintaffar JL, Arnhof H, Wunberg T, Sgubin D, Arnold A, Vekariya RH, Christov PP, Kim K, Fuchs JE, Karier P, Betzemeier B, Van Meveren M, Miriyala N, Olejniczak ET, Engelhardt H, Lee T, McConnell D, Fesik SW J Med Chem. 2025 Sep 11;68(17):18553-18578. doi: 10.1021/acs.jmedchem.5c01376. , Epub 2025 Aug 27. PMID:40864607<ref>PMID:40864607</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9pw6" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fesik SW]]
[[Category: Zhao B]]