TY - JOUR
T1 - IFITM proteins assist cellular uptake of diverse linked chemotypes
AU - Lou, Kevin
AU - Wassarman, Douglas R.
AU - Yang, Tangpo
AU - Paung, Yi Ting
AU - Zhang, Ziyang
AU - O'Loughlin, Thomas A.
AU - Moore, Megan K.
AU - Egan, Regina K.
AU - Greninger, Patricia
AU - Benes, Cyril H.
AU - Seeliger, Markus A.
AU - Taunton, Jack
AU - Gilbert, Luke A.
AU - Shokat, Kevan M.
N1 - Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.
PY - 2022/12/9
Y1 - 2022/12/9
N2 - The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.
AB - The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.
UR - https://www.scopus.com/pages/publications/85143563686
U2 - 10.1126/science.abl5829
DO - 10.1126/science.abl5829
M3 - Article
C2 - 36480603
AN - SCOPUS:85143563686
SN - 0036-8075
VL - 378
SP - 1097
EP - 1104
JO - Science
JF - Science
IS - 6624
ER -