PF-4989216

• CAT Number: I001102
• CAS Number: 1276553-09-3
• Molecular Formula: C₁₈H₁₃FN₆OS
• Molecular Weight: 380.4
• Purity: ≥95%
• Synonyms: 4-(4-cyano-2-fluorophenyl)-2-morpholino-5-(1H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile
• Target: PI3K
• Solubility: DMSO: ≥ 29 mg/mL
• Storage: Store at -20°C
• IC50: 0.6 nM (Ki, PI3Kalpha), 1440 nM (Ki, mTOR) [1]
• IUPAC Name: 4-(4-cyano-2-fluorophenyl)-2-morpholin-4-yl-5-(1H-1,2,4-triazol-5-yl)thiophene-3-carbonitrile
• InChI: InChI=1S/C18H13FN6OS/c19-14-7-11(8-20)1-2-12(14)15-13(9-21)18(25-3-5-26-6-4-25)27-16(15)17-22-10-23-24-17/h1-2,7,10H,3-6H2,(H,22,23,24)
• InChIKey: MUENOTXSRZEFJV-UHFFFAOYSA-N
• SMILES: C1COCCN1C2=C(C(=C(S2)C3=NC=NN3)C4=C(C=C(C=C4)C#N)F)C#N

PF-4989216（Cat No.:I001102） is a highly potent and selective inhibitor of phosphoinositide 3-kinase (PI3K), an enzyme involved in various cellular processes including cell growth, proliferation, and survival. It exhibits excellent inhibitory activity against different isoforms of PI3K, with IC50 values of 2 nM for p110α, 142 nM for p110β, 65 nM for p110γ, 1 nM for p110δ, and 110 nM for VPS34. The compound’s selectivity and strong inhibitory activity make it a promising candidate for the development of targeted therapies against diseases associated with dysregulated PI3K signaling, such as cancer.

Reference

1:Clin Cancer Res. 2014 Feb 1;20(3):631-43. doi: 10.1158/1078-0432.CCR-13-1663. Epub 2013 Nov 15. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor PF-4989216.Walls M,Baxi SM,Mehta PP,Liu KK,Zhu J,Estrella H,Li C,Zientek M,Zong Q,Smeal T,Yin MJ, PMID: 24240111 DOI: 10.1158/1078-0432.CCR-13-1663 Abstract: PURPOSE: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation.EXPERIMENTAL DESIGN: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment.RESULTS: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss.CONCLUSIONS: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss.©2013 AACR.