171179-06-9

PD 158780 is a potent tyrosine kinase inhibitor of the epidermal growth factor receptor and has been shown to delay substantial growth of tumors in vivo tumor models.

ChEBI: PD158780 is a pyridopyrimidine that is pyrido[3,4-d]pyrimidine-4,6-diamine in which the amino groups at positions 4 and 6 are substituted by a m-bromophenyl group and a methyl group, respectively. It is a potent, cell-permeable, reversible ATP-competitive inhibitor of EGFR tyrosine kinase activity [IC50 values of 0.008, 49 and 52 nM for EGFR, ErbB2 (HER2) and Erb4 (HER4)]. It does not inhibit FGF or PDGF-mediated tyrosine phosphorylation. Induces G1 cell cycle arrest in MCF10A cells and is antiproliferative in A431 human epidermal carcinoma cells. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a pyridopyrimidine, a secondary amino compound, a member of bromobenzenes, a diamine and an aromatic amine.

A potent inhibitor of the EGFR tyrosine kinase activity (8 pM). Also inhibits heregulin-stimulated autophosphorylation in SK-BR-3 (IC₅₀ =49 nM) and MDA-MB-453 (IC₅₀ = 52 nM) breast carcinomas. The inhibition is competitive and results from binding of the inhibitor at the ATP site of the enzymes. Inhibits the LPA-stimulated MAP kinase kinase 1/2 (MKK1/2) activation and EGFR tyrosine phosphorylation in HeLa and NIH3T3 cells.

Potent inhibitor of ErbB receptor family tyrosine kinases (IC 50 values are 0.008, 49 and 52 nM for EGFR, ErbB2 and ErbB2/ErbB4 respectively) that does not inhibit FGF or PDGF-mediated tyrosine phosphorylation. Induces G 1 cell cycle arrest in MCF10A cells and is antiproliferative in A431 human epidermal carcinoma cells.

Cell permeable: yes

Example 60: Synthesis of N4-(3-bromophenyl)-N6-methylpyrido[3,4-d]pyrimidine-4,6-diamine N-(3-Bromophenyl)-6-fluoro-pyrido[3,4-D]pyrimidin-4-amine (0.20 g, 0.63 mmol) was placed in a pressure vessel and an ethanol solution of methylamine was added and reacted at 100 °C. After completion of the reaction, purification was carried out by alumina column chromatography with the eluent dichloromethane/methanol (99:1, v/v) to afford the target product N4-(3-bromophenyl)-N6-methylpyrido[3,4-d]pyrimidine-4,6-diamine (0.07 g, 34% yield). 1H NMR (DMSO) δ 9.69 (1H, s), 8.75 (1H, s), 8.41 (1H, s), 8.21 (1H, brs), 7.93 (1H, brd, J = 7.6 Hz), 7.41-7.28 (2H, m), 7.06 (1H, s), 6.82 (1H, q, J = 5.0 Hz), 4.95 ( 3H, d, J = 5.0 Hz).

Store at -20°C

[1] Patent: US5654307, 1997, A