TY - JOUR
T1 - Design, synthesis, and biological evaluation of HDAC degraders with CRBN E3 ligase ligands
AU - Lu, Yingxin
AU - Sun, Danwen
AU - Xiao, Donghuai
AU - Shao, Yingying
AU - Su, Mingbo
AU - Zhou, Yubo
AU - Li, Jia
AU - Zhu, Shulei
AU - Lu, Wei
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).
AB - Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).
KW - Benzyl alcohol linkage
KW - CRBN ligands
KW - HDAC degraders
KW - Proteins of interest
UR - https://www.scopus.com/pages/publications/85120169213
U2 - 10.3390/molecules26237241
DO - 10.3390/molecules26237241
M3 - 文章
C2 - 34885822
AN - SCOPUS:85120169213
SN - 1420-3049
VL - 26
JO - Molecules
JF - Molecules
IS - 23
M1 - 7241
ER -
