Building on a well-documented drug design process, we have joined together several pharmacophores with the goal of developing anticancer compounds with enhanced activity and tolerable side effects. These potent anticancer small molecules have a simple 3-component A-B-C-structure with molecular weights in the 500-700 Dalton range. Since inflammation is well-documented in the risk and etiology of cancer, it is not surprising that there are numerous experimental, epidemiological and clinical studies which suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit anticancer drug effects, although with modest single agent activity. Thus, we have incorporated flurbiprofen and ibuprofen as the A components in our new multitargeted A-B-C peptidomimetics. Strikingly, we discovered that the A-B-C compound containing flurbiprofen at position A was 1200 times more potent against lung cancer cell lines than the parent flurbiprofen compound. Based on previous studies in our laboratory, we have demonstrated the anticancer properties of the biphenyl-alanyl moiety at position B and the sterically-hindered cyclic amine antioxidant moiety at position C (1). This antioxidant moiety at position C has been shown to possess antitumor activity against various cell lines and to also enhance chemotherapy-induced apoptosis (1,2). Recently, 18 of our A-B-C type compounds were tested in the NCI 60 cancer cell line study where compound GH501 (Fig. 1) exhibited potent anticancer activity against a wide variety of cancer cell lines, including leukemia, non-small cell (NSC) lung, colon, CNS, ovarian, renal, prostate, breast and melanoma. The IC50
values were in the sub-micromolar range (477 nM on average for the 9 cancer types and 60 cell
lines). Although based upon this screen GH501 exhibits broad anticancer activity, we have selected melanoma as the initial disease focus, where despite recent advancements, there still remain few therapeutic options for treating advanced disease and the prognosis for patients is poor. The efficacy of GH501 was further explored against additional melanoma cell lines by Drs. Eckhardt and Tentler. As depicted in Fig. 2, GH501 demonstrates potent anticancer activity against melanoma cell lines with IC50 values of 202-772 nM for 7/9 cell lines, which compares favorably to the IC50 values of 122-428 nM for 6/8 melanoma cell lines in the NCI screen. Thus, a total of 17 distinct melanoma cell lines have been screened in two independent studies. Of note, GH501 was effective against cell lines harboring the V600E BRAF mutation (3) as well as wild-type BRAF suggesting activity independent of BRAF status. The next steps required to position GH501 for clinical development include 1) preliminary toxicology studies, 2) assessment of mechanism of action, and 3) in vivo efficacy studies in patient-derived models of melanoma (4).
References 1. Stewart JM, Gera L, Chan DC, York EJ, Simkeviciene V, Bunn PA Jr, Taraseviciene-Stewart L. Peptides 26(8): 1288-1291 (2005). 2. Wasserman V, Kizelsztein P, Garbuzenko O, Kohen R, Ovadia H, Tabakman R, and Barenholz Y. Langmuir 23(4): 1937-1947 (2007). 3. Chapman, PB, Hauschild, A, Robert, C. et al. New England Journal of Medicine 364(26): 2507-2516 (2011). 4. Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG. Nature Reviews Clinical Oncology 9(6): 338-35(2012).