AZ7550, an Active Metabolite of AZD9291 (EGFR TKI), Inhibits the Activity of IGF1R

By Edward Jenner 2020-10-10 #EGFR, #H1975, #IGF1R, #PC9, #T790M

Lung cancer still remains the most common cancer-related mortality worldwide with about 80-85% of patients suffering from non-small cell lung cancer (NSCLC). The EGFR is currently the most established molecular target in NSCLC; approximately 10%-15% and 50% of tumors in Caucasian and Asian patient populations, respectively, harbor mutations in the EGFR. EGFR is a member of the ErbB family of structurally related RTKs, consisting of the EGFR (ErbB1), as well as ErbB2, ErbB3and ErbB4. These proteins form an array of homo- or heterodimers at the cell surface and play a key role in the normal physiological regulation of cellular proliferation. The development and progression of many human cancers, including NSCLC, have relations with aberrant ErbB family signaling. AZD-9291 is an irreversible and mutant selective EGFR inhibitor, with activities against EGFRL858R and EGFRL858R/T790M, respectively. In this study, AZ7550 is an active metabolite of AZD9291 and inhibits the activity of IGF1R.

AZ7550 is an active metabolite of AZD9291 and inhibits the activity of IGF1R.

AZ7550 appears to offer a broadly similar potency and selectivity profile to the parent compound AZD9291. Moreover, AZ7550 inhibits double mutant (DM) cell line H1975, activating mutant (AM) cell line PC9, and wild type (WT) cell line LoVo with IC₅₀s of 45, 26, and 786 nM, respectively. It also inhibits DM antiproliferative cell line H1975, AM antiproliferative cell line PC9, and WT antiproliferative cell line Calu3. The GI₅₀s are 19, 15, and 537 nM, respectively. In addition, it also inhibits the activity of IGF1R with an IC50 of 1.6 μM. IGF1R is a class II receptor tyrosine kinase (RTK) belonging to the insulin receptor family, and it plays a critical role in cell growth and differentiation.

In summary, AZ7550 is an active metabolite of AZD9291. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Thus, AZ7550 has the potential for NSCLC treatment.

Reference:

Finlay MR, et al. J Med Chem. 2014 Oct 23;57(20):8249-67.

By Edward Jenner

Cancer Immunology Immune