Young-Gil Ahn

Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel.

Multi-drug resistance 1 (MDR1, ABCB1), also known as P-glycoprotein (P-gp), restricts intestinal uptake of many drugs, and contributes to cellular resistance to cancer chemotherapy. In this study, we examined the pharmacologic characteristics of HM30181, a newly developed MDR1 inhibitor, and tested its capacity to increase the oral bioavailability and efficacy of paclitaxel, an anti-cancer drug usually given by intravenous injection. In the ATPase assay using MDR1-enriched vesicles, HM30181 showed the highest potency (IC(50)=0.63nM) among several MDR1 inhibitors, including cycloporin A, XR9576, and GF120918, and effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM). The ATPase inhibitory activity of HM30181 was highly selective to MDR1. HM30181 did not inhibit MRP1 (ABCC1), MRP2 (ABCC2), and MRP3 (ABCC3), and partially inhibited BCRP (ABCG2) only at very high concentrations. Importantly, co-administration of HM30181 (10mg/kg) greatly increased oral bioavailability of paclitaxel from 3.4% to 41.3% in rats. Moreover, oral co-administration of paclitaxel and HM30181 showed a tumor-inhibitory strength equal or superior to that of intravenous paclitaxel in the xenograft model in nude mice. These results identify HM30181 as a highly selective and potent inhibitor of MDR1, which in combination with paclitaxel, may provide an orally effective anti-tumor regimen.

Abstract 2606: Antitumor activity of the selective RAF inhibitor HM95573 in melanoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF and NRAS is considered one of the causes of melanoma. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of mutant BRAF melanoma cell lines such asA375 (IC50: 57nM) and SK-MEL-28 (69nM) and of mutant NRAS melanoma cell lines such asSK-MEL-2 (53nM) and SK-MEL-30 (24nM). In addition, the phosphorylations of MEK and ERK downstream kinases associated with cell proliferation were effectively inhibited with treatment of HM95573in mutant BRAF and mutant NRAS melanoma cells.HM95573inhibited the downstream signaling in melanoma cells even in the presence of HGF which is known to mediate innate resistance to RAF inhibitors. HM95573 showed the excellent antitumor activity in mouse models xenografted with both of BRAF mutation cell lines (e.g. A375 and SK-MEL-28) and NRAS mutation cell lines (such as SK-MEL-2 and SK-MEL-30) compared to two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. Furthermore, HM95573 did not show a potential to paradoxical activation inducing tumor growth in mouse xenograft study using A431 cuSCC (cutaneous squamous cell carcinoma)cancer cell. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including melanoma in Korea. Citation Format: InHwan Bae, YoungGil Ahn, Namgoong GwangMo, SuHyeon Kim, JiYeon Song, TaeHun Song, JaeHo Lee, KyuHang Lee, Young-Mi Lee, YoungHoon Kim, KweeHyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2015-2606

KMS88009 and KMS88016 as small molecule inhibitors for in vivo Aβ fibril formation

YoungSoo Kim, Ji Hun Byun, Jiyeon Ryu, Hana Hwang, Ji Hoon Lee, Jeiwon Cho, HyeYun Kim, Young-Gil Ahn, Young Hoon Kim, Maeng Sup Kim, Gwan Sun Lee, Inhee Mook-Jung, Kyung Ho Yoo, Dong Jin Kim, Korea Institute of Science and Technology, Seoul, Republic of Korea; Hanmi Research Center, Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea; Seoul National University College of Medicine, Seoul, Republic of Korea. Contact e-mail: yskim@kist.re.kr