Hidetoshi Shindoh

The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor

The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F–driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations. Mol Cancer Ther; 13(11); 2547–58. ©2014 AACR.

Preclinical evaluation of the potential for cytochrome P450 inhibition and induction of the selective ALK inhibitor, alectinib.

Abstract 1.u2002A novel selective anaplastic lymphoma kinase (ALK) inhibitor, alectinib, has shown remarkable efficacy and safety in patients with ALK-positive non-small-cell lung cancer (NSCLC). The purpose of this study was to evaluate in vitro the potential to inhibit and induce cytochrome P450 (CYP) isoforms for alectinib and its major metabolite M4. 2.u2002Alectinib and M4 did not show the meaningful direct inhibition of six major CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) in human liver microsomes (HLM). Alectinib, but not M4, competitively inhibited CYP2C8, by which few marketed drugs are exclusively metabolized, with an inhibition constant of 1.98u2009μM. 3.u2002Out of the seven CYP isoforms in HLM, alectinib and M4 showed time-dependent inhibition (TDI) of only CYP3A4, which suggests low TDI potential due to low inactivation efficiency. 4.u2002Alectinib exhibited quite smaller induction of mRNA expression of CYP1A2, 2B6 and 3A4 genes in human hepatocytes compared to the respective positive controls, suggesting a low potential of enzyme induction. 5.u2002In summary, the risk of alectinib causing drug-drug interactions with coadministered drugs is expected to be low due to the weak potential of CYP inhibition and induction estimated in the preclinical studies.

Enantioselective synthesis of derivatives and structure-activity relationship study in the development of NA255 as a novel host-targeting anti-HCV agent.

Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed. The structure-activity relationship of the NA255 derivatives and rat pharmacokinetic profiles of the representative compounds are disclosed.

Simple Evaluation Method for CYP3A4 Induction from Human Hepatocytes: The Relative Factor Approach with an Induction Detection Limit Concentration Based on the Emax Model

We investigated the robustness and utility of the relative factor (RF) approach based on the maximum induction effect (Emax) model, using the mRNA induction data of 10 typical CYP3A4 inducers in cryopreserved human hepatocytes. The RF value is designated as the ratio of the induction detection limit concentration (IDLC) for a standard inducer, such as rifampicin (RIF) or phenobarbital (PB), to that for the compound (e.g., RFRIF is IDLCRIF/IDLCcpd; RFPB is IDLCPB/IDLCcpd). An important feature of the RF approach is that the profiles of the induction response curves on the logarithmic scale remain unchanged irrespective of inducers but are shifted parallel depending on the EC50 values. A key step in the RF approach is to convert the induction response curve by finding the IDLC of a standard inducer. The relative induction score was estimated not only from Emax and EC50 values but also from those calculated by the RF approach. These values showed good correlation, with a correlation coefficient of more than 0.974, which revealed the RF approach to be a robust analysis irrespective of its simplicity. Furthermore, the relationship between RFRIF or RFPB multiplied by the steady-state unbound plasma concentration and the in vivo induction ratio plotted using 10 typical inducers gives adequate thresholds for CYP3A4 drug-drug interaction risk assessment. In light of these findings, the simple RF approach using the IDLC value could be a useful method to adequately assess the risk of CYP3A4 induction in humans during drug discovery and development without evaluation of Emax and EC50.

Abstract 2729: FGFR genetic alterations as a potential predictor of the sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor with a novel chemical scaffold

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnThe fibroblast growth factor receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplification, point mutation, or chromosomal translocation/rearrangement. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGFR or PDGFR family showed some clinical benefits in FGFR genetically altered patient populations. However, to achieve more potent and prolonged efficacy in such populations, a selective FGFR inhibitor is still needed.nnHere, we report identifying CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold as a FGFR inhibitor. By interacting with unique residues in the ATP binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 (IC50: 9.3 nM, 7.6 nM, and 22 nM), but does not effectively inhibit FGFR4 (IC50: 290 nM ), KDR (IC50: 2,100 nM) or other 34 kinases. At 100 nM, CH5183284/Debio 1347 only binds to 5 kinases in the KinomeScan panel, including FGFR1, FGFR2, and FGFR3. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 does not lead to significant changes in blood pressure in telemetry-instrumented rats. In addition, CH5183284/Debio 1347 has a preferential antitumor activity against cancer cells with FGFR genetic alterations in a panel of 327 cancer cell lines. Among them, 4 cancer cell lines have copy number variations (CNV) of FGFR1 (>2.2 fold), 2 cancer cell lines have chromosomal translocation of FGFR1 (FGFR1OP-FGFR1), 6 cancer cell lines have CNV of FGFR2 (>2.2 fold), 3 cancer cell lines have point mutation of FGFR2 (S252W, K310R, N549K), 3 cancer cell lines have chromosomal translocation of FGFR3 (FGFR3-TACC3, FGFR3-BAIAP2L1), and 2 cancer cell lines have point mutation of FGFR3 (S249C, Y373C). This preferential efficacy against cancers harboring genetic alterations in FGFR was also confirmed in mouse xenograft studies. These findings warrant further investigation of CH5183284/Debio 1347 in patients harboring FGFR genetic alterations. Clinical studies have been initiated.nnCitation Format: Yoshito Nakanishi, Nukinori Akiyama, Toshiyuki Tsukaguchi, Yukako Tachibana-Kondo, Toshihiko Fujii, Kiyoaki Sakata, Hitoshi Sase, Takehito Isobe, Yasuko Sato, Kenji Morikami, Hidetoshi Shindoh, Toshiyuki Mio, Hirosato Ebiike, Naoki Taka, Yuko Aoki, Nobuya Ishii. FGFR genetic alterations as a potential predictor of the sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor with a novel chemical scaffold. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2729. doi:10.1158/1538-7445.AM2014-2729