Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations

Tang, Yigang; Song, Huaxin; Wang, Zhengyuan; Xiao, Shujun; Xiang, Xinrong; Zhan, Huien; Wu, Lili; Wu, Jiale; Xing, Yangfei; Tan, Yun; Liang, Ying; Ni, Yaodong; Li, Yuntong; Li, Jiabing; Wu, Jiaqi; Zheng, Derun; Jia, Yunchuan; Chen, Zhiming; Li, Yunqi; Zhang, Qianqian; Zhang, Jianming; Zeng, Hui; Tao, Wei; Liu, Feng; Wu, Yu; Lü, Min

doi:10.1016/j.celrep.2022.110622

Cited by 20 publications

(24 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 431 PAT – Temperature-sensitive mutants: V272M, P278A, Q136P and so on. 432 ZMC1 – R175H 441 UCI-LC0023 – R175H 462 PhiKan083 PhiKan5196 PK7088 (PK7242) Compound9 Compound6 PK11007 MB710 L5 PK9318 LI LH PC14586 – Y220C 467 – 478 ReAcp53 R248Q R175H 490 ADH-6 R248W – 496 Peptide 46 R273H – 549 CDB3 R273H R175H, G245S, R249S 507 , 510 pCAPs R273H R175H, R280H and so on. 511 …”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

“…Potassium antimony tartrate (PAT) was identified as binding to the p53 V272M mutant (Kd = 9.09 μM) in a non-covalent manner, increasing its thermostability by 3.6 °C and remarkably restoring protein folding and transcriptional activity. 432 PAT is an antiparasitic agent that has been used as a treatment for leishmaniasis, 433 , 434 and has since been found to have antitumor activity. 435 , 436 PAT is similar to ATO in that both can induce apoptosis in APL cells.…”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

“…9d ), but differ in two aspects, with PAT non-covalently binding mutant p53 and preferentially rescuing temperature-sensitive mutants (a subtype of structural mutants), whereas ATO covalently binding mutant p53 and apparently rescuing more structural p53 mutants. 432 Notably, the ATO and PAT studies comprehensively and experimentally compared the set of representative mutant p53-rescuing compounds. PAT exhibited specific p53 V272M antitumor activity in both cellular and xenograft mouse models.…”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

“…Further testing identified 65 of p53 mutants that could be rescued by PAT, but all were non-hotspot mutations. 432 A clinical trial of antimony for the treatment of MDS/AML with TP53 mutations is currently underway.…”

Section: Structure-based P53 Targetingmentioning

confidence: 99%

See 3 more Smart Citations

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

157

View full text Add to dashboard Cite

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the “guardian of the genome”. Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an “undruggable” target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.

show abstract

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Section: Structure-based P53 Targetingmentioning

confidence: 99%

Section: Structure-based P53 Targetingmentioning

confidence: 99%

See 2 more Smart Citations

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

157

View full text Add to dashboard Cite

show abstract

“…Hsp-mediated stabilization is a highly effective strategy employed by nature and has demonstrated efficacy toward stabilization of thermolabile p53 mutants. , The effectiveness of this strategy for protein reactivation reveals an opportunity to achieve a similar effect using synthetic additives (pharmacological chaperoning). Despite recent successes in the development of small-molecule drug candidates that operate through p53 reactivation, many suffer key drawbacks like high toxicity (Nutlins, COTI-2, arsenic trioxide), nonspecific oxidative damage (APR-246, ZMC1, PK11007), or PAIN motifs (ZMC1, COTI-2). − The so-called “Holy Grail” of p53 drug discovery, a nontoxic cancer-selective reactivator of transcription, thus remains a prime target, and research into Y220C stabilizers paves the way toward generic chaperones that may be applicable to the 2–3 million annual cancer cases related to unstable mutant p53 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C

Clarke¹,

Douglas

Duriez

et al. 2022

ACS Pharmacol. Transl. Sci.

View full text Add to dashboard Cite

The tumor suppressor protein p53 is inactivated in the majority of human cancers and remains a prime target for developing new drugs to reactivate its tumor suppressing activity for anticancer therapies. The oncogenic p53 mutant Y220C accounts for approximately 125,000 new cancer cases per annum and is one of the most prevalent p53 mutants overall. It harbors a narrow, mutationally induced pocket at the surface of the DNA-binding domain that destabilizes p53, leading to its rapid denaturation and aggregation. Here, we present the structure-guided development of high-affinity small molecules stabilizing p53-Y220C in vitro, along with the synthetic routes developed in the process, in vitro structure− activity relationship data, and confirmation of their binding mode by protein X-ray crystallography. We disclose two new chemical probes displaying sub-micromolar binding affinity in vitro, marking an important milestone since the discovery of the first small-molecule ligand of Y220C in 2008. New chemical probe JC744 displayed a K d = 320 nM, along with potent in vitro protein stabilization. This study, therefore, represents a significant advance toward highaffinity Y220C ligands for clinical evaluation.

show abstract

Synergistic rescue of temperature‐sensitive p53 mutants by hypothermia and arsenic trioxide

Lu,

Chen,

Fatima

et al. 2024

Molecular Carcinogenesis

View full text Add to dashboard Cite

The p53 tumor suppressor is inactivated by mutations in about 50% of tumors. Rescuing the transcriptional function of mutant p53 has potential therapeutic benefits. Approximately 15% of p53 mutants are temperature sensitive (TS) and regain maximal activity at 32°C. Proof of concept study showed that induction of 32°C hypothermia in mice restored TS mutant p53 activity and inhibited tumor growth. However, 32°C is the lower limit of therapeutic hypothermia procedures for humans. Higher temperatures are preferable but result in suboptimal TS p53 activation. Recently, arsenic trioxide (ATO) was shown to rescue the conformation of p53 structural mutants by stabilizing the DNA binding domain. We examined the responses of 17 frequently observed p53 TS mutants to functional rescue by temperature shift and ATO. The results showed that ATO only rescued mild p53 TS mutants with high basal activity at 37°C. Mild TS mutants showed a common feature of regaining significant activity at the semi‐permissive temperature of 35°C and could be further stimulated by ATO at 35°C. TS p53 rescue by ATO was antagonized by the cellular redox mechanism and was rapidly reversible. Inhibition of glutathione (GSH) biosynthesis enhanced ATO rescue efficiency and sustained p53 activity after ATO washout. The results suggest that mild TS p53 mutants are uniquely responsive to functional rescue by ATO due to small thermostability deficits and inherent potential to regain active conformation. Combining mild hypothermia and ATO may provide an effective and safe procedure for targeting tumors with p53 TS mutations.

show abstract

Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations

Cited by 20 publications

References 83 publications

Targeting p53 pathways: mechanisms, structures and advances in therapy

Targeting p53 pathways: mechanisms, structures and advances in therapy

Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C

Synergistic rescue of temperature‐sensitive p53 mutants by hypothermia and arsenic trioxide

Contact Info

Product

Resources

About