TY - JOUR
T1 - Discovery of MK-4688
T2 - An Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction
AU - Reutershan, Michael H.
AU - MacHacek, Michelle R.
AU - Altman, Michael D.
AU - Bogen, Stephane
AU - Cai, Mingmei
AU - Cammarano, Carolyn
AU - Chen, Dapeng
AU - Christopher, Matthew
AU - Cryan, John
AU - Daublain, Pierre
AU - Fradera, Xavier
AU - Geda, Prasanthi
AU - Goldenblatt, Peter
AU - Hill, Armetta D.
AU - Kemper, Raymond A.
AU - Kutilek, Victoria
AU - Li, Chaomin
AU - Martinez, Michelle
AU - McCoy, Mark
AU - Nair, Latha
AU - Pan, Weidong
AU - Thompson, Christopher F.
AU - Scapin, Giovanna
AU - Shizuka, Manami
AU - Spatz, Marianne L.
AU - Steinhuebel, Dietrich
AU - Sun, Binyuan
AU - Voss, Matthew E.
AU - Wang, Xiao
AU - Yang, Liping
AU - Yeh, Tammie C.
AU - Dussault, Isabelle
AU - Marshall, C. Gary
AU - Trotter, B. Wesley
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/11/11
Y1 - 2021/11/11
N2 - Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
AB - Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
UR - https://www.scopus.com/pages/publications/85118823933
U2 - 10.1021/acs.jmedchem.1c01524
DO - 10.1021/acs.jmedchem.1c01524
M3 - Scientific article
C2 - 34714078
AN - SCOPUS:85118823933
SN - 0022-2623
VL - 64
SP - 16213
EP - 16241
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -