PK11007

• CAT Number: I046075
• CAS Number: 874146-69-7
• Molecular Formula: C15H11ClFN5O3S2
• Molecular Weight: 427.86
• Purity: ≥95%
• Synonyms: 5-chloro-2-[(4-fluorophenyl)methylsulfonyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide
• InChI: InChI=1S/C15H11ClFN5O3S2/c1-8-21-22-14(26-8)20-13(23)12-11(16)6-18-15(19-12)27(24,25)7-9-2-4-10(17)5-3-9/h2-6H,7H2,1H3,(H,20,22,23)
• InChIKey: IVZQUWCWXYFPOQ-UHFFFAOYSA-N
• SMILES: CC1=NN=C(S1)NC(=O)C2=NC(=NC=C2Cl)S(=O)(=O)CC3=CC=C(C=C3)F

PK11007 is a mild thiol alkylator with anticancer activity. PK11007 stabilizes p53 via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. PK11007 induces mutant p53 cancer cell death by increasing reactive oxygen species (ROS) levels[1][2].
PK11007 (0-120 µM; 24 hours; four p53 wild-type cell lines and fours p53 mutant cell lines) treatment results in a large viability reduction in mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S) at concentrations ranging from 15 to 30 µM. PK11007 induces mainly caspase-independent cell death[1].
PK11007 (0-60 µM; 3 hours or 6 hours; NUGC-4, NUGC-3, MKN1, HUH-6, and HUH-7 cancer cells) treatment up-regulates protein levels of the p53 target genes p21, MDM2, and PUMA in a mostly concentration-dependent manner in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C) and MKN1 (p53-V143A) cells, suggesting partial restoration of transcriptional activity to destabilized p53 mutants. PK11007 also increases p53 activity in HUH-6 and NUGC-4 cells, as indicated by the increase of MDM2, PUMA, and p21 protein levels[1].
PK11007 (15-20 µM; 4.5 hours or 6 hours; MKN1, HUH-7, NUGC-3, HUH-6 cells) treatment increases transcription of p53 target genes in three mutant p53 cell lines after 6-h treatment. PUMA and p21 mRNA levels are up-regulated by a factor of 2 upon treatment of NUGC-3, MKN, and HUH-7 cells, as well as NOXA for the latter two. MDM2 levels are halved in MKN1 and NUGC-3 cells[1].
PK11007 viability reduction is potentiated by glutathione depletion. To test whether PK11007 also increases ROS levels, NUGC-3, NUGC-4, HUH-6, HUH-7, and MKN1 cells with PK11007 are incubated for 2 h. There are elevated ROS levels in all cell lines after 2 h. In the mutant p53 cells MKN1, HUH-7, and NUGC-3, however, the ROS increase is higher at 60 µM PK11007 than in NUGC-4 and HUH-6 cells, suggesting that the higher PK11007 sensitivity of the mutant p53 cell lines is mediated by a stronger ROS induction. Basal and PK11007-induced ROS levels in MKN1 cells are at least twofold higher than in other cell lines[1].
PK11007 inhibits cell proliferation, induces apoptosis and alters genes involved in cell death are all consistent with the ability of PK11007 to reactivate mutant p53[2].

Reference

[1]. Bauer MR, et al. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):E5271-80.
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[2]. Synnott NC, et al. Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Preclinical investigation with the anti-p53 drug, PK11007. Cancer Lett. 2018 Feb 1;414:99-106
 [Content Brief]