2. Academic Validation
  3. 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.
PMID: 34965125 DOI: 10.1021/acs.jmedchem.1c01832
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z