EGFR inhibitors

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G Marciano R, Ciardiello F, Tortora G. (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98 923-930. 

Ciardiello F, De Vita F, Qrditura M, et al. The role of EGFR inhibitors in nonsmall cell lung cancer. Curr Opin Oncol 2004 16 130-5. 

Two other amino-acid substitutions, G719S and L861Q, as well as small in-frame insertions, within exon 20, account for the remaining 5% of mutations. Furthermore, it has become evident that the frequency of EGFR mutations within the NSCLC patient population correlates very closely with the 10% response rate to EGFR TKls (49). This provides some credence to the notion that these mutations confer hypersensitivity to the EGFR inhibitors. 

Because the T790M mutation affects the ability of reversible TKIs to bind to EGFR, it follows that irreversible inhibitors may circumvent this problem. Irreversible EGFR inhibitors such as HKI-272, HKI-357, and a compound developed by Wyeth Research, EKB-569, have shown some early efficacy (81,91,92). These compounds form covalent bonds with the EGFR protein at a distinct cysteine residue C773, within the kinase... 

Haber DA, Bell DW, Sordella R et al. Molecular targeted therapy of lung cancer EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol 2005 70 419-426. 

Cavasotto, C. N., Ortiz, M. A., Abagyan, R. A., Piedrafita, F. J. (2006) In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells. Bioorg Med Chem Lett 16,1969-1974. 

Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006 6(10) 803-812. 

Fig. 10. Chemical structures of kinase inhibitors, (a) p38 inhibitor SB203580 (4-[5-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-3H-imidazol-4-yl]pyridine). (b) EGFR inhibitor (N-(3-(6-(3-(trifluoromethyl) phenylamino) pyrimidin-4-ylamino) phenyl) cydopropanecarboxamide). The dashed line indicates hydrogen-bonding interactions with the hinge.

A number of design strategies have been applied to EGFR inhibitors and have made it into the clinic and, in the case of lapatinib, onto the market. Due to... 

---