For research use only.
CAS No. 5291-32-7
APR-246, also known as PRIMA-1MET, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. APR-246 induces apoptosis and autophagy.
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|Description||APR-246, also known as PRIMA-1MET, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. APR-246 induces apoptosis and autophagy.|
APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wild-type conformation. APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. It not only reactivates p53 but also decreases intracellular glutathione levels in a dose-dependent manner. APR-246 can trigger apoptosis in a p53-independent manner by inducing ROS and endoplasmic reticulum (ER) stress and by inhibiting thioredoxin reductase 1 (TrxR1). It was also reported that APR-246 induces cell death in myeloma cells independently of p53 status by impairing the GSH/ROS balance. PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells.
|In vivo||APR-246 showed a good safety profile in a Phase I/II clinical dose-finding study on hematological malignancies and prostate cancer and both clinical and p53-dependent biological responses were observed. In animal studies, APR-246 is well tolerated. Single treatment with APR-246 inhibits tumor growth by 21% in mice bearing the aggressively growing A2780-CP20 tumor xenografts.|
|In vitro||DMSO||40 mg/mL (200.75 mM)|
|Water||40 mg/mL (200.75 mM)|
|Ethanol||40 mg/mL (200.75 mM)|
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT04383938||Recruiting||Drug: APR-246 (eprenetapopt) + Pembrolizumab||Bladder Cancer|Gastric Cancer|Non Small Cell Lung Cancer|NSCLC|Urothelial Carcinoma|Advanced Solid Tumor||Aprea Therapeutics||June 25 2020||Phase 1|Phase 2|
|NCT04214860||Recruiting||Drug: APR-246|Drug: Venetoclax|Drug: Azacitidine||Myeloid Malignancy||Aprea Therapeutics||December 13 2019||Phase 1|
|NCT03745716||Active not recruiting||Drug: APR-246 + azacitidine|Drug: Azacitidine||MDS||Aprea Therapeutics||January 11 2019||Phase 3|
|NCT03391050||Terminated||Drug: APR-246|Drug: Dabrafenib||Melanoma||Aprea Therapeutics|Jules Bordet Institute||January 18 2018||Phase 1|Phase 2|
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