Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities

Uesato, Shinichi; Matsuura, Yoshimitsu; Matsue, Saki; Sumiyoshi, Takaaki; Hirata, Y.; Takemoto, Suzuho; Kawaratani, Yasuyuki; Yamai, Yu‐suke; Ishida, Kyoji; Sasaki, Tsutomu; Enari, Masato

doi:10.1016/j.bmc.2016.03.021

Cited by 12 publications

(13 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More and more researchers invest in the discovery of natural-product and rationally designed MDMX inhibitors and demonstrate their anticancer efficacy and mechanism(s) of action in preclinical cancer models in vitro and in vivo . Their main focus has been on the design and development of p53-MDMX binding inhibitors by targeting the p53-binding pocket of MDMX, such as SAH-p53-8 ( 92 ), mSF-SAH ( 93 ), SJ-172550 ( 94 ), compound B1 ( 96 ), CTX1 ( 97 ), and K-178 ( 98 ). All these inhibitors exert their anticancer activity through activating wild-type p53 and the transcription of its downstream target genes related to cell cycle arrest (e.g., p21) and apoptosis (e.g., Puma and Bax).…”

Section: Discussionmentioning

confidence: 99%

“…Due to advances in understanding the structure and binding mechanisms of p53-MDM2 and p53-MDMX complexes, many inhibitors have been developed to dually inhibit the interactions of p53-MDM2/MDMX, which have been comprehensively discussed in the recent review articles ( 26 – 29 ). Several specific p53-MDMX binding inhibitors, including, but not limited to, SAH-p53-8 ( 92 ), SJ-172550 ( 94 ), compound B1 ( 96 ), CTX1 ( 97 ), and K-178 ( 98 ) have recently been discovered and shown promising anticancer efficacy and safety profiles in preclinical models in vitro and in vivo ( Table 2 ). Bernal et al have designed and synthesized a stapled p53 helix, named SAH-p53-8 that specifically binds to MDMX with strong affinity ( K D = 2.3 nM) ( 92 ).…”

Section: Mdmx Inhibitors In Preclinical Studiesmentioning

confidence: 99%

“…The lead compound K-178 has been shown to activate the p53 signaling and inhibit the viability of cancer cell lines with wild-type p53 and overexpressing MDMX, including human breast (MCF-7), lung (A427), and colon (HCT116) cancer cell lines. It has also been demonstrated that K-178 suppresses tumor growth in an HCT116 xenograft mouse model without affecting the average mouse body weight during the treatment period ( 98 ). Further studies on both CTX1 and K-178 in more clinically relevant cancer models are needed for the further development of these MDMX inhibitors as anticancer drugs.…”

Section: Mdmx Inhibitors In Preclinical Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Mdmx Inhibitors In Preclinical Studiesmentioning

confidence: 99%

Section: Mdmx Inhibitors In Preclinical Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…101 Two analogues, K-178 and K-181 (Figure 18, 37 and 38), inhibited MDM4/p53 interaction with IC 50 values of 1.5 and 4.6 μM. 102 On the other hand, K-178 and K-181 inhibited MDM2/p53 interaction with IC 50 values of 13.1 and 14.6 μM. In MCF-7 cells, K-178 dose-dependently increased protein levels of MDM2 and p53.…”

Section: Small-molecule Inhibitors That Block Mdm4-p53 Protein−protei...mentioning

confidence: 99%

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Zhang

Lou

et al. 2021

J. Med. Chem.

View full text Add to dashboard Cite

MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/ MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.

show abstract

“…The training set of inhibitors (total 293) with experimental IC 50 values [33][34][35][36][37][38][39][40][41][42][43][44], which have been tested with human Mdmx, were selected from the ChEMBL and BindingDB [45] databases. Their IC 50 values were measured by several kinds of methods, The average Tanimoto similarity within the dataset is 0.56.…”

Section: Mdmx Inhibitorsmentioning

confidence: 99%

Focused Library Generator: case of Mdmx inhibitors

Xia

Karpov

Popowicz

et al. 2019

J Comput Aided Mol Des

View full text Add to dashboard Cite

We present a Focused Library Generator that is able to create from scratch new molecules with desired properties. After training the Generator on the ChEMBL database, transfer learning was used to switch the generator to producing new Mdmx inhibitors that are a promising class of anticancer drugs. Lilly medicinal chemistry filters, molecular docking, and a QSAR IC 50 model were used to refine the output of the Generator. Pharmacophore screening and molecular dynamics (MD) simulations were then used to further select putative ligands. Finally, we identified five promising hits with equivalent or even better predicted binding free energies and IC 50 values than known Mdmx inhibitors. The

show abstract

Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities

Cited by 12 publications

References 30 publications

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Focused Library Generator: case of Mdmx inhibitors

Contact Info

Product

Resources

About