IFITM proteins assist cellular uptake of diverse linked chemotypes

Kevin Lou; Douglas R Wassarman; Tangpo Yang; YiTing Paung; Ziyang Zhang; Thomas A O'Loughlin; Megan K Moore; Regina K Egan; Patricia Greninger; Cyril H Benes; Markus A Seeliger; Jack Taunton; Luke A Gilbert; Kevan M Shokat

doi:10.1126/science.abl5829

IFITM proteins assist cellular uptake of diverse linked chemotypes

Science. 2022 Dec 9;378(6624):1097-1104. doi: 10.1126/science.abl5829. Epub 2022 Dec 8.

Authors

Kevin Lou^{1

2}, Douglas R Wassarman^{1

2}, Tangpo Yang¹, YiTing Paung³, Ziyang Zhang^{1

2

4}, Thomas A O'Loughlin^{5

6}, Megan K Moore^{1

2}, Regina K Egan⁷, Patricia Greninger⁷, Cyril H Benes^{7

8}, Markus A Seeliger³, Jack Taunton¹, Luke A Gilbert^{5

6

9

10}, Kevan M Shokat^{1

2

4}

Affiliations

¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
² Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
⁴ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
⁸ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Innovative Genomics Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁰ Arc Institute, Palo Alto, CA 94304, USA.

Abstract

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.

Abstract

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