194423-06-8

Overactivity of epidermal growth factor receptor (EGFR) tyrosine kinase activity has been associated with a number of cancers. CL 387,785 is a potent, irreversible inhibitor of EGFR kinase activity (IC₅₀ = 370 pM). It blocks EGF-stimulated autophosphorylation of receptors in cells (IC₅₀ = 5 nM) and halts cell cycling in cells that overexpress EGFR or c-ErbB2 (IC₅₀s = 31-125 nM). CL 387,785 profoundly blocks the growth of EGFR-overexpressing tumors in nude mice when given orally at 80 mg/kg/day for 10 days.

Irreversibly inhibits EGF-stimulated autophosphorylation of tyrosine residues in the epidermal growth factor receptor (EGFR) in vivo (IC50=250-490pM) and blocks EGF-mediated growth.

ChEBI: A member of the class of quinazolines that is 4,6-diaminoquinazoine in which the one of the hydrogens attached to the amino group at position 4 has been replaced by a m-bromophenyl group while one of the hydrogens attached to the amino group a position 6 has been replaced by a but-2-ynoyl group.

General procedure for the synthesis of N-(4-((3-bromophenyl)amino)quinazolin-6-yl)but-2-ynamide from 2-butynoic acid and N4-(3-bromophenyl)quinazoline-4,6-diamine: 2-butynoic acid (196 mg, 2.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (385 mg, 2.0 mmol ) were dissolved in DMF (5 mL) and stirred at 25 °C for 20 min. Subsequently 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol) was added. The reaction mixture was stirred under nitrogen protection at 25 °C for 14 hours. After that, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (206 mg, 1.0 mmol) and 2-butynoic acid (82 mg, 1.0 mmol) were added again and stirring was continued for 8 hours. Next, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg, 1.0 mmol) and 2-butynoic acid (93 mg, 1.0 mmol) were added for the third time and stirred for another 12 h at 25 °C. After completion of the reaction, the reaction was quenched with water. The resulting yellow precipitate was collected, sonicated with acetone and treated with triethylamine. Finally, it was purified by preparative thin layer chromatography on silica gel using 1:1 EtOAc/acetone as eluent. The target product was isolated as a yellow solid (20 mg, 4.7% yield) with a melting point of 281-283 °C. 1H NMR [(CD3)2SO]: δ 10.97 (brs, 1H, NH), 9.93 (s, 1H, NH), 8.76 (s, 1H, H5), 8.57 (s, 1H, H2), 8.14 (s, 1H, H2'). 7.84-7.76 (m, 3H, H7, H8, H4'), 7.34 (t, J = 8.1 Hz, 1H, H5'), 7.29 (d, J = 7.8 Hz, 1H, H6'), 2.09 (s, 3H, CH3). Mass spectrum (APCI): 383 (100, 81BrMH+), 382 (23, 81BrM+), 381 (95, 79BrMH+). Calculated values for elemental analysis (C18H13N4BrO-0.3HCl-0.6C3H6O): C, 55.69; H, 3.99; N, 13.12%. Measured values: C, 55.67; H, 3.96; N, 12.93%.

cl-387785 covalently bound to egfr. it also specifically inhibited kinase activity of the protein, blocked egf-stimulated autophosphorylation of the receptor in cells, inhibited cell proliferation primarily in a cytostatic manner in cell lines that overexpress egf-r or c-erbb-2 [1].

the effects of cl-387785 on tumor growth were assessed in human tumor xenografts implanted s.c. in the flanks of nude mice. cl-387785 inhibited the growth of tumors derived from a431 cells when the drug was administered i.p. or p.o.. inhibitory effects were observed within 7 days after the onset of therapy. no efficacy was observed with cl-387785 in tumors derived from cell lines that did not overexpress egf-r, including the human breast carcinoma mda-mb-435 [1].

370 pm

[1] discafani cm, carroll ml, floyd mb jr, hollander ij, husain z, johnson bd, kitchen d, may mk, malo ms, minnick aa jr, nilakantan r, shen r, wang yf, wissner a, greenberger lm. irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by n-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (cl-387,785). biochem pharmacol. 1999 apr 15;57(8):917-25.