Discovery of a potent dual EGFR/HER-2 inhibitor L-2 (selatinib) for the treatment of cancer

• A series of new lapatinib analogs were designed, synthesized and tested.
• A potent dual EGFR/HER2 inhibitor L-2 has been identified.
• In NCI-N87 and SK-OV-3 xenografts, L-2 inhibited tumor growth by 94.8% and 85.7%.
• L-2 has improved pharmacokinetic profiles (relative bioavailability 187%).
• A high-yielding one-pot procedure was developed for the synthesis of these analogs.

To develop potent dual EGFR/HER-2 inhibitors with improved druggability, a series of new lapatinib analogs were designed and synthesized. Compared with lapatinib, L-2, L-4 and M-6 were more active against BT-474 or NCI-N87 cells. In vivo efficacy studies indicated that L-2 significantly suppressed tumor growth in NCI-N87 (94.8% inhibition) or SK-OV-3 xenograft (85.7% inhibition) without causing significant loss of body weight. And the inhibition rates of lapatinib in the two xenograft models were 89.7% and 78.8%, respectively. Moreover, further studies revealed that the potent in vivo activities of L-2 may be mainly attributed to its superior aqueous solubility and oral bioavailability. In addition, a high-yielding one-pot procedure was developed for the synthesis of lapatinib and its analogs.

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