1. Academic Validation
  2. Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216

Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216

  • J Med Chem. 2022 Jan 13;65(1):747-756. doi: 10.1021/acs.jmedchem.1c01832.
Mingxing Teng 1 Wenchao Lu 2 Katherine A Donovan 1 3 Jialin Sun 1 3 Noah M Krupnick 1 Radosław P Nowak 1 3 Yen-Der Li 4 5 Adam S Sperling 4 5 Tinghu Zhang 2 Benjamin L Ebert 4 5 6 Eric S Fischer 1 3 Nathanael S Gray 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 4 Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 6 Howard Hughes Medical Institute, Boston, Massachusetts 02215, United States.
Abstract

Immunomodulatory drugs are a class of drugs approved for the treatment of multiple myeloma. These compounds exert their clinical effects by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and a C2H2 zinc finger degron motif, resulting in degradation of degron-containing targets. However, although many cellular proteins feature the degron motif, only a subset of those are degradable via this strategy. Here, we demonstrated that FPFT-2216, a previously reported "molecular glue" compound, degrades PDE6D, in addition to IKZF1, IKZF3, and CK1α. We used FPFT-2216 as a starting point for a focused medicinal chemistry campaign and developed TMX-4100 and TMX-4116, which exhibit greater selectivity for degrading PDE6D and CK1α, respectively. We also showed that the region in PDE6D that interacts with the FPFT-2216 derivatives is not the previously pursued prenyl-binding pocket. Moreover, we found that PDE6D depletion by FPFT-2216 does not impede the growth of KRASG12C-dependent MIA PaCa-2 cells, highlighting the challenges of drugging PDE6D-KRAS. Taken together, the approach we described here represents a general scheme to rapidly develop selective degraders by reprogramming E3 ubiquitin ligase substrate specificity.

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