Maeng Sup Kim

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.

Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models†

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in‐frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non‐small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan‐HER inhibitor, HM781‐36B. The results from this study show that HM781‐36B is a potent inhibitor of EGFR in vitro, including the EGFR‐acquired resistance mutation (T790M), as well as HER‐2 and HER‐4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781‐36B treatment of EGFR DelE746_A750‐harboring erlotinib‐sensitive HCC827 and EGFR L858R/T790M‐harboring erlotinib‐resistant NCI‐H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781‐36B shows an excellent efficacy in a variety of EGFR‐ and HER‐2‐dependent tumor xenograft models, including erlotinib‐sensitive HCC827 NSCLC cells, erlotinib‐resistant NCI‐H1975 NSCLC cells, HER‐2 overexpressing Calu‐3 NSCLC cells, NCI‐N87 gastric cancer cells, SK‐Ov3 ovarian cancer cells and EGFR‐overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781‐36B is the most potent pan‐HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors

Virtual screening was performed to determine potent vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitors. A database of approximately 820,000 commercial compounds was used for screening, and 100 compounds were chosen as candidate VEGFR-2 inhibitors through pharmacophore modeling and docking studies. These 100 compounds were purchased to test their biological activities: 10 compounds were found to inhibit the enzyme, with IC(50) values ranging from 10 to 1 μM. Compound 1, which has a triazinoindole ring, inhibited the enzymatic activity of VEGFR-2, with an IC(50) value of about 1.6 μM, making it the most potent inhibitor of this enzyme. The triazinoindole derivative may therefore serve as the starting point in the design of new VEGFR-2 kinase inhibitors.

Discovery of A Novel Her-1/Her-2 Dual Tyrosine Kinase Inhibitor for the Treatment of Her-1 Selective Inhibitor-Resistant Non-small Cell Lung Cancer

A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.

Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases.

A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.

Aminostyrylbenzofuran directly reduces oligomeric amyloid-β and reverses cognitive deficits in Alzheimer transgenic mice.

Alzheimers disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-β into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-β aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4-dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-β oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimers disease symptoms, KMS88009 significantly reduced assembly of amyloid-β oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimers disease.

Motion planning of eye, hand and body of humanoid robot

This paper presents an algorithm for planning the motions of a sensor and a manipulator that are kinematically connected. Humanoid robots or other service robots have a vision system and one or two arms, and they are usually mounted on a single body. Given a task to be performed, the robot needs to plan a short, collision-free motion for the arm while placing the camera for optimal viewing conditions so the task progress can be monitored. Since they are kinematically connected, motion of the camera affects the motion of the arm, or the arm may block the view of the camera. Our algorithm plans the body posture, camera motion and the manipulator motion that allows occlusion-free viewing of a target point and placement of the hand at a target hand location. It uses robots kinematic redundancy to avoid collisions and occlusion of the view point. Since the ensemble of the camera actuator and the manipulator has many joints, the search is performed in the world space rather than in the high-dimensional joint space. The global nature of our search algorithm enables finding a solution in most practical cases.

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer’s disease treatment

Alzheimers disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.

Abstract 4660: Antiproliferative effects of antagonists of Inhibitor of Apoptosis Proteins (IAPs) in human cancer cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The inhibitor of apoptosis (IAP) proteins are a family of proteins containing one or more conserved, cysteine and histidine-rich baculoviral IAP repeat (BIR) N-terminal domains and a C-terminal RING domain The BIR domains of the IAPs form the zinc-figure-like structures that bind to active caspases to block caspase activity. The RING domain acts as an ubiquitin ligase to facilitate proteasomal degradation of caspases. Upregulation of IAPs is found in many tumor cell lines as well as in most primary tumor tissues. Increased expression of IAPs has been associated with apoptosis resistance and low sensitivity to chemotherapy drugs in several tumor types. Recent studies have shown that inhibition of levels or functions of survivin and/XIAP with anti-sense, siRNA, and dominant negative mutant survivin genes induces the apoptotic cell death selectively in human tumor cells but not in normal cells. Like such, the importance of IAPs in regulating the apoptotic response and as molecular targets for production of therapeutic effects selectively in tumor cells have attracted a great attention to identify peptide antagonists or small molecule inhibitors for those proteins. In the effort to develop efficient antagonists of IAPs into chemotherapy drug, we analyzed the apoptotic effect of HM antagonists, novel small molecules inhibiting IAP activities, on non-small-cell lung cancer cells and colon cells. We also analyzed changes in cell signaling pathways after HM antagonists treatment to determine the mechanisms of the apoptotic response in cancer cells. Finally, the feasibility of using HM antagonists to sensitize human cancer cells to chemotherapy drugs was examined by combining HM antagonists with two commonly used agents, cisplatin and MK2206. In the present study, we have demonstrated that this reagent efficiently decreased IAPs expression in several NSCLC cells, especially on EGFR activated cells, as well as colon cells. It showed cleaved caspase 3 and PARP, and decreasing phosphor-Akt and phosphor-Erk, indicating that the reagents exerted antiapoptotic activity through inhibition of Akt and MAPK signaling pathways. Ongoing xenograft experiments using NSCLC cells and colon cells would manifest the potential chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4660. doi:1538-7445.AM2012-4660

Abstract LB-389: Antitumor activity of HM781–36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. But clinical treatment is limited by the development of drug resistance resulting mainly from an acquired mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781–36B. We demonstrated that HM781–36B is a potent EGFR inhibitor including the EGFR -acquired resistance mutation (IC 50 4.2 nM in EGFR T790M and IC 50 2.2 nM in EGFR L858R/T790M ), as well as EGFR, HER-2 and HER-4 (IC 50 3.2 nM, 5.3 nM and 23.5 nM, respectively), compared to other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW-2992), with kinase selectivity confirmed by 77 kinases panel assay except for Blk, Bmx and Btk. Strong growth inhibitory activity by the treatment of HM781–36B was confirmed with the range of IC 50 0.6–6nM in NSCLC (HCC827, H358, H1975, Calu-3, and H1781), breast cancer (SK-Br3, BT474, MDA-175, and MDA-453), and gastric cancer (N87 and SNU-216) cell lines. HM781–36B showed 400–4,000 fold low growth inhibitory effect against normal cell lines (Hs-27 and Balb/c 3T3) relative to cancer cell lines. HM781–36B treatment results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins in EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells. HM781–36B interacts directly with its target enzyme ( EGFR WT , EGFR T790M , HER-2), which was confirmed through prolongation study of phosphorylation inhibitory effect in A431 and SK-Br3 cells and direct fluorescence-based SDS-PAGE analysis by the incubation of Cy3-labeled HM781–36B probe. This irreversible occupation at the kinase domain leads to excellent in vivo efficacy of HM781–36B (1mg/kg – 5mg/kg) toward various xenograft models with EGFR-dependent cancers cells, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, N87 gastric cancer cells, and SK-Ov3 ovarian cancer cells, and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781–36B was selected as a candidate for clinical development and a phase I study of HM781–36B is currently undergoing in South Korea. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-389. doi:10.1158/1538-7445.AM2011-LB-389