2024
Simple Fluorescence Labeling Method Enables Detection of Intracellular Distribution and Expression Level of Retinoid X Receptors
Yukina Tanaka, Michiko Fujihara, Yuta Takamura, Mayu Kawasaki, Shogo Nakano, Makoto Makishima, and Hiroki Kakuta*
ACS Med. Chem. Lett. 2024 doi.org/10.1021/acsmedchemlett.4c00033


2023
Direct evaluation of polarity of the ligand binding pocket in retinoid X receptor using a fluorescent solvatochromic agonist.
Miura K, Fujihara M, Watanabe M, Takamura Y, Kawasaki M, Nakano S, Kakuta H.
Bioorg Med Chem Lett. 2023 Oct 30;96:129536. doi: 10.1016/j.bmcl.2023.129536.

Characterization and Interconversion of Two Crystal Forms of NEt-3IB, a Retinoid X Receptor Agonist
Yuta Takamura, Shota Kikuzawa, Michiko Fujihara, Yukinari Sunatsuki, Kazutaka Higaki, Hiroki Kakuta*
Chem. Pharm. Bull. 2023, 71, 282–288.

Ligand Screening System for the RXR Heterodimer Using the Fluorescence RXR Agonist CU-6PMN
Mayu Kawasaki; Tomoharu Motoyama; Shoya Yamada; Masaki Watanabe; Michiko Fujihara; Akira Kambe; Shogo Nakano*; Hiroki Kakuta*; Sohei Ito*
ACS Med. Chem. Lett. 2023, 14, 291–296.


2022
Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha
Susumu Kodama, Shuzo Matsumoto, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Atsushi Ono, Hiroki Kakuta
Toxicol Lett. 2022, 373:76-83. doi: 10.1016/j.toxlet.2022.11.003.

Analysis of absorption-enhancing mechanisms for combinatorial use of spermine with sodium taurocholate in Caco-2 cells
Masato Maruyama, Yohei Nishida, Hironori Tanaka, Takako Minami, Ken-Ichi Ogawara, Masateru Miyake, Yuta Takamura, Hiroki Kakuta , Kazutaka Higaki
Eur J Pharm Biopharm. 2022 S0939-6411, 00247-8.

Teratogenicity and Fetal-Transfer Assessment of the Retinoid X Receptor Agonist Bexarotene
Yuta Takamura, Izumi Kato, Manami Fujita-Takahashi, Midori Azuma-Nishii, Masaki Watanabe, Rui Nozaki, Masaru Akehi, Takanori Sasaki, Hiroyuki Hirano, and Hiroki Kakuta*
ACS Pharmacology & Translational Science, 2022, 5, 811-818
Press release from Okayama University (Japanese only)

Identification of a vitamin-D receptor antagonist, MeTC7, which inhibits the growth of xenograft and transgenic tumors in vivo
Khazan, Negar; Kim, Kyu Kwang; Hansen, Jeanne; Singh, Niloy; Moore, Taylor; Snyder, Cameron; Pandita, Ravina; Strawderman, Myla; Fujihara, Michiko; Takamura, Yuta; Jian, Ye; Battaglia, Nicholas ; Yano, Naohiro; Teramoto, Yuki; Arnold, Leggy; Hopson, Russell; Kishor, Keshav; Nayak, Sneha; Ojha, Debasmita; Sharon, Ashoke; Ashton, John; Wang, Jian; Milano, Michael; Miyamoto, Hiroshi; Linehan, David; Gerber, Scott; Kawar, Nada; Singh, Ajay Pratap; Tabdanov, Erdem; Dokholyan, Nikolay; Kakuta*, Hiroki; Jurutka, Peter; Schor*, Nina F.; Rowswell-Turner , Rachael; Singh*, Rakesh; Moore , Richard.
J. Med. Chem. 2022, 65, 8, 6039–6055.

Development of Scaled-up Synthetic Method for Retinoid X Receptor Agonist NEt-3IB Contributing to Sustainable Development Goals
Takamura Y, Morishita KI, Kikuzawa S, Watanabe M, Kakuta H.
Chem. Pharm. Bull. 2022, 70, 146–154.
Press release from Okayama University (Japanese)
Press release from Okayama University (English)

Increased Molecular Flexibility Widens the Gap between Ki and Kd values in Screening for Retinoid X Receptor Modulators
Watanabe M, Nakamura-Nakayama M, Fujihara M, Kawasaki M, Nakano S, Kakuta H.
ACS Med. Chem. Lett. 2022, 13, 211–217.


2021
A retinoid X receptor agonist directed to the large intestine ameliorates T-cell-mediated colitis in mice
Matsumoto R, Takahashi D, Watanabe M, Nakatani S, Takamura Y, Kurosaki Y, Kakuta H, Hase K.
Front. Pharmacol. 2021, 12, 715752.

Creation of Fluorescent RXR Antagonists Based on CBTF-EE and Application to Fluorescence Polarization Binding Assay
Takioku M, Takamura Y, Fujihara M, Watanabe M, Yamada S, Kawasaki M, Ito S, Nakano S, Kakuta H.
ACS Med. Chem. Lett. 2021, 12, 1024–1029.

In Vivo Receptor Visualization and Evaluation of Receptor Occupancy with Positron Emission Tomography
Takamura Y, Kakuta H.
J. Med. Chem. 2021, 64, 5226–5251. Perspective (review).

Convenient Retinoid X Receptor Binding Assay Based on Fluorescence Change of the Antagonist NEt-C343
Yukawa-Takamatsu K, Wang Y, Watanabe M, Takamura Y, Fujihara M, Nakamura-Nakayama M, Yamada S, Kikuzawa S, Makishima M, Kawasaki M, Ito S, Nakano S, Kakuta H.
J. Med. Chem. 2021, 64, 861–870.

Discovery of a “Gatekeeper” Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers
Watanabe M, Fujihara M, Motoyama T, Kawasaki M, Yamada S, Takamura Y, Ito S, Makishima M, Nakano S, Kakuta H.
J. Med. Chem. 2021, 64, 430-439.

Fluorescence properties of retinoid X receptor antagonist NEt-SB
Yamada S, Takamura Y, Fujihara M, Kawasaki M, Ito S, Nakano S, Kakuta H.
Bioorg. Med. Chem. Lett. 2021, 31,127666.


2020
Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells
Nawara HM, M Afify S, Hassan G, Zahra MH, Atallah MN, Mansour H, Abu Quora HA, Alam MJ, Osman A, Kakuta H, Hamada H, Seno A, Seno M.
Cancers (Basel). 2020, 12, 1360.

Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice.
Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K.
Science. 2020, 367, eaaw8429.


2019
Competitive Binding Assay with an Umbelliferone-based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening.
Yamada S, Kawasaki M, Fujihara M, Watanabe M, Takamura Y, Takioku M, Nishioka H, Takeuchi Y, Makishima M, Motoyama T, Ito S, Tokiwa H, Nakano S, Kakuta H.
J. Med. Chem. 2019, 62, 8809–8818.

Fluorine-18-labeled Retinoid X Receptor (RXR) Partial Agonist whose Tissue Transferability is Affected by Other RXR Ligands
Takamura Y, Shibahara O, Watanabe M, Fujihara M, Yamada S, Akehi M, Sasaki T, Hirano H, Kakuta H.
Bioorg. Med. Chem. 2019, 27, 3128–3134.

3H-Imidazo[4,5-b]pyridine-6-carboxylic Acid Derivatives as Rexinoids with Reduced Teratogenicity
Takamura Y, Takahashi M, Nishii M, Shibahara O, Watanabe M, Fujihara M, Kakuta H.
Bioorg. Med. Chem. Lett. 2019, 29, 1891–1894.

Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets.
Itaba N, Kono Y, Watanabe K, Yokobata T, Oka H, Osaki M, Kakuta H, Morimoto M, Shiota G.
Sci. Rep. 2019, 9, 6841.

A partial agonist for retinoid X receptor mitigates experimental colitis.
Onuki M, Watanabe M, Ishihara N, Suzuki K, Takizawa K, Hirota M, Yamada T, Egawa A, Shibahara O, Nishii M, Fujihara M, Makishima M, Takahashi D, Furusawa Y, Kakuta H, Hase K.
Int. Immunol. 2019, 31, 251–262.

Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor a (RXRa)
Miyashita Y, Numoto N, Aulmozhiraja S, Nakano S, Matsuo N, Shimizu K, Shibahara O, Fujihara M, Kakuta H, Ito S, Ikura T, Ito N, Tokiwa H.
FEBS Lett. 2019, 593, 242–250.

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation.
Morichika D, Miyahara N, Fujii U, Taniguchi A, Oda N, Senoo S, Kataoka M, Tanimoto M, Kakuta H, Kiura K, Maeda Y, Kanehiro A.
Respir. Res. 2019, 20, 2.


2018
Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer.
Rosati R, Polin L, Ducker C, Li J, Bao X, Selvakumar D, Kim S, Xhabija B, Larsen M, McFall T, Huang Y, Kidder BL, Fribley A, Saxton J, Kakuta H, Shaw P, Ratnam M.
Clin. Cancer Res. 2018, 24, 6509–6522.

Retinoid X Receptor Antagonist.
Watanabe M, Kakuta H.
Int. J. Mol. Sci. 2018, 19, 2354. Review.


2017
Synthesis of 11C-Labeled RXR Partial Agonist 1-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [11C]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof.
Shibahara O, Watanabe M, Yamada S, Akehi M, Sasaki T, Akahoshi A, Hanada T, Hirano H, Nakatani S, Nishioka H, Takeuchi Y, Kakuta H.
J. Med. Chem. 2017, 60, 7139–7145. (ADITION / CORRECTION: J. Med. Chem. 2019, 62, 4780–4781.)

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma.
Fujii U, Miyahara N, Taniguchi A, Oda N, Morichika D, Murakami E, Nakayama H, Waseda K, Kataoka M, Kakuta H, Tanimoto M, Kanehiro A.
Respir. Res. 2017, 18, 23.

Retinoid X Receptor Ligands with Anti-Type 2 Diabetic Activity.
Morishita KI, Kakuta H.
Curr. Top Med. Chem. 2017, 17, 696–707. Review.


2016
iPSC-derived cancer stem cells provide a model of tumor vasculature.
Prieto-Vila M, Yan T, Calle AS, Nair N, Hurley L, Kasai T, Kakuta H, Masuda J, Murakami H, Mizutani A, Seno M.
Am. J. Cancer Res. 2016, 6, 1906–1921.


2015
Positron Emission Tomography to Elucidate Pharma-cokinetic Differences of Regioisomeric Retinoid X Receptor Agonists
Kobayashi T, Furusawa Y, Yamada S, Akehi M, Takenaka F, Sasaki T, Akahoshi A, Hanada T, Matsuura E, Hirano H, Tai A, and Kakuta H.
ACS Med. Chem. Lett. 2015, 6, 334–338.

RXR Partial Agonist Produced by Side-Chain Repositioning of Alkoxy RXR Full Agonist Retains Anti-type 2 Diabetes Activity without the Adverse Effects.
Kawata K, Morishita KI, Yamada S, Nakayama M, Kobayashi T, Furusawa Y, Arimoto-Kobayashi S, Oohashi T, Makishima M, Naitou H, Ishitsubo E, Tokiwa H, Tai A, Kakuta H.
J. Med. Chem. 2015, 58, 912–926.


2014
Involvement of glucocorticoid receptor activation on anti-inflammatory effect induced by peroxisome proliferator-activated receptor γ agonist in mice.
Yamamoto A, Kakuta H, Sugimoto Y.
Int. Immunopharmacol. 2014, 22, 204–208.

In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.
El-Aarag BY, Kasai T, Zahran MA, Zakhary NI, Shigehiro T, Sekhar SC, Agwa HS, Mizutani A, Murakami H, Kakuta H, Seno M.
Int. Immunopharmacol. 2014, 21, 283–292.

Retinoid X receptor ligands: a patent review (2007-2013).
Yamada S, Kakuta H.
Expert Opin. Ther. Pat. 2014, 24, 443–452. Review

Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes.
Murakami Y, Shimizu Y, Ogasawara A, Ueshima S, Nakayama M, Kawata K, Kakuta H, Aiba T.
Drug Dev. Ind. Pharm. 2014, 40, 1065–1071.


2013
Mechanism of Retinoid X Receptor Partial Agonistic Action of 1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic Acid and Structural Development To Increase Potency.
Ohsawa F, Yamada S, Yakushiji N, Shinozaki R, Nakayama M, Kawata K, Hagaya M, Kobayashi T, Kohara K, Furusawa Y, Fujiwara C, Ohta Y, Makishima M, Naitou H, Tai A, Yoshikawa Y, Yasui H, Kakuta H*.
J. Med. Chem. 2013, 56, 1865–1877.


2012
RXR partial agonist CBt-PMN exerts therapeutic effects on type 2 diabetes without the side effects of RXR full agonists.
Kakuta H*, Yakushiji N, Shinozaki R, Ohsawa F, Yamada, S, Ohta Y, Kawata K, Nakayama M, Hagaya M, Fujiwara C, Makishima K, Uno S, Tai A, Maehara A, Nakayama M, Oohashi T, Yasui H, Yoshikawa Y.
ACS Med. Chem. Lett. 2012, 3, 427–443.

Feasibility of Structural Modification of RXR Agonists to Separate Blood Glucose-Lowering Action from Adverse Effects: Studies in KKAy Type 2 Diabetes Model Mice.
Kakuta H, Ohsawa F, Yamada S, Makishima M, Tai A, Yasui H, Yoshikawa Y.
Biol. Pharm. Bull. 2012, 35, 629–633.

Relevance of nuclear receptor expression in a Tchreg cell line, HOZOT: RXRα and PPARγ negatively regulate IFN-γ production.
Suzuki M, Takeuchi M, Tsuji-Takayama K, Harashima A, Otani T, Toraya T, Kakuta H, Yamasaki F,  Nakamura S, Kibata M.
Results in Immunol. 2012, 2, 158–165.


2011
Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor γ Agonist In Vivo.
Yamamoto A, Kakuta H, Miyachi H, Sugimoto Y.
PPAR Res. 2011, 2011, 840194.

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.
Nakayama M, Yamada S, Ohsawa F, Ohta Y, Kawata K, Makishima M, and Kakuta H.
ACS Med. Chem. Lett. 2011, 2, 896–900.

Replacement of the hydrophobic part of 9-cis-retinoic acid with cyclic terpenoid moiety results in RXR-selective agonistic activity.
Okitsu T, Sato K, Iwatsuka K, Sawada N, Nakagawa K, Okano T, Yamada S, Kakuta H, Wada A*
Bioorg. Med. Chem. 2011, 19, 2939–2949.

Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats.
Ogasawara A, Murakami Y, Murakami Y, Yakushiji N, Ohsawa N, Kusaba J, AIba T, Kurosaki Y, Kakuta H.
Drug Dev. Ind. Pharm. 2011, 37, 1060–1067.

Design and Synthesis of Novel Cyclooxygenase-1 Inhibitors as Analgesics: 5-Amino-2-ethoxy-N-(substituted-phenyl)benzamides.
Fukai R, Zheng X, Motoshima K, Tai A, Yazama F, Kakuta H.
ChemMedChem 2011, 6, 550–560.

An Arylidene-Thiazolidinedione Derivative, GPU-4, without PPARγ Activation, Reduces Retinal Neovascularization.
Nakamura S, Hayashi K, Takizawa H, Murase T, Tsuruma K, Shimazawa M, Kakuta H, Nagasawa H, Hara H.
Curr. Neurovasc. Res. 2011, 8, 25–34.


2010
Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers
Ohsawa F, Morishita K, Yamada S, Makishima M, Kakuta H.
ACS Med. Chem. Lett. 2010, 1, 521–525.

Cyclic-tri(N-methyl-meta-benzamide)s: substituent effects on the bowl-shaped conformation in the crystal and solution states
Kakuta H, Azumaya I, Masu H, Matsumura M, Yamaguchi K, Kagechika H, Tanatani A.
Tetrahedron 2010, 66, 8254–8260.

Fluorescent retinoid X receptor ligands for fluorescence polarization assay.
Yamada S, Ohsawa F, Fujii S, Shinozaki R, Makishima M, Naitou H, Enomoto S, Tai A, Kakuta H.
Bioorg. Med. Chem. Lett. 2010, 20, 5143–5146.

Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation.
Fujii S, Ohsawa F, Yamada S, Shinozaki R, Fukai R, Makishima M, Enomoto S, Tai A, Kakuta H.
Bioorg. Med. Chem. Lett. 2010, 20, 5139–5142.

Effect of 5-aminosalicylate on allergic rhinitis model in mice.
Kuyama S, Yamamoto A, Sugiyama M, Kakuta H, Sugimoto Y.
Int. Immunopharmacol. 2010, 10, 713–716.

Identification of urine metabolites of TFAP, a cyclooxygenase-1 inhibitor.
Kakuta H, Fukai R, Xiaoxia Z, Ohsawa F, Bamba T, Hirata K, Tai A.
Bioorg. Med. Chem. Lett. 2010, 20, 1840–1843.


2009
Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity.
Morishita K, Yakushiji N, Ohsawa F, Takamatsu K, Matsuura N, Makishima M, Kawahata M, Yamaguchi K, Tai A, Sasaki K, Kakuta H.
Bioorg. Med. Chem. Lett. 2009, 19, 1001–1003.


2008
Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum.
Yoshikawa M, Motoshima K, Fujimoto K, Tai A, Kakuta H, Sasaki K.
Bioorg. Med. Chem. 2008, 16, 6027–6033.

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
Namba K, Zheng X, Motoshima K, Kobayashi H, Tai A, Takahashi E, Sasaki K, Okamoto K, Kakuta H.
Bioorg. Med. Chem. 2008, 16, 6131–6144.

Necessity is the mother of invention: an ingenious method for leukocyte-targeted delivery of siRNA in stabilized nanoparticles demonstrates a role of cyclin D1 in inflammation.
Kakuta H.
ChemMedChem 2008, 3, 1024–1025.

Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation.
Zheng X, Oda H, Harada S, Sugimoto Y, Tai A, Sasaki K, Kakuta H
J. Pharm. Sci. 2008, 97, 5446–5452.

Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor.
Kakuta H, Zheng X, Oda H, Harada S, Sugimoto Y, Sasaki K, Tai A.
J. Med. Chem. 2008, 51, 2400–2411.

The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist).
Takamatsu K, Takano A, Yakushiji N, Morohashi K, Morishita K, Matsuura N, Makishima M, Tai A, Sasaki K, Kakuta H.
ChemMedChem 2008, 3, 780–787.

Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXRalpha-preferential agonist possessing a sulfonamide moiety.
Takamatsu K, Takano A, Yakushiji N, Morishita K, Matsuura N, Makishima M, Ali HI, Akaho E, Tai A, Sasaki K, Kakuta H.
ChemMedChem 2008, 3, 454–460.


2007
Antimalarial cation-dimers synthesized in two steps from an inexpensive starting material, isonicotinic acid.
Motoshima K, Hiwasa Y, Yoshikawa M, Fujimoto K, Tai A, Kakuta H, Sasaki K.
ChemMedChem 2007, 2, 1527–1532.

Antimalarial effect of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide).
Fujimoto K, Morisaki D, Yoshida M, Namba T, Hye-Sook K, Wataya Y, Kourai H, Kakuta H, Sasaki K.
Bioorg. Med. Chem. Lett. 2006, 16, 2758–2760.

Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors.
Zheng X, Oda H, Takamatsu K, Sugimoto Y, Tai A, Akaho E, Ali HI, Oshiki T, Kakuta H, Sasaki K.
Bioorg. Med. Chem. 2007, 15, 1014–1021. (Erratum in: Bioorg. Med. Chem. 2007, 15, 3299–3300.)


2004
Membrane permeabilization by non-steroidal anti-inflammatory drugs.
Tomisato W, Tanaka K, Katsu T, Kakuta H, Sasaki K, Tsutsumi S, Hoshino T, Aburaya M, Li D, Tsuchiya T, Suzuki K, Yokomizo K, Mizushima T.
Biochem. Biophys. Res. Commun. 2004, 323, 1032–1039.