Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.
Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy.
Aileron Therapeutics, Inc., Cambridge, MA 02139, USA. ychang@aileronrx.com
Yong S
YS
Chang
Bradford
B
Graves
Vincent
V
Guerlavais
Christian
C
Tovar
Kathryn
K
Packman
Kwong-Him
KH
To
Karen A
KA
Olson
Kamala
K
Kesavan
Pranoti
P
Gangurde
Aditi
A
Mukherjee
Theresa
T
Baker
Krzysztof
K
Darlak
Carl
C
Elkin
Zoran
Z
Filipovic
Farooq Z
FZ
Qureshi
Hongliang
H
Cai
Pamela
P
Berry
Eric
E
Feyfant
Xiangguo E
XE
Shi
James
J
Horstick
D Allen
DA
Annis
Anthony M
AM
Manning
Nader
N
Fotouhi
Huw
H
Nash
Lyubomir T
LT
Vassilev
Tomi K
TK
Sawyer
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C584947:ATSP-7041; D000970:Antineoplastic Agents; D010455:Peptides; D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2