Prospective Study on relationship between CD73 expression in biliary tract cancer and response to anticancer drugs and the underlying biological mechanisms - Prospective Study on relationship between CD73 expression in biliary tract cancer and its progression and prognosis, and the underlying biological mechanisms

Start Date28 Jun 2023

Sponsor / Collaborator

Hokkaido University

100 Clinical Results associated with XX-650-23

100 Translational Medicine associated with XX-650-23

100 Patents (Medical) associated with XX-650-23

Literatures (Medical) associated with XX-650-23

01 Aug 2019·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway

Q4 · MEDICINE

Article

Author: Kam, Sharon ; Liu, Corey W ; Ng, Andrew A ; Smith, Mark ; Cox, Nick ; Lee, Jae Wook ; Potter, Garrett ; Edwards, Jeffrey ; Sakamoto, Kathleen M ; Lee, Yvonne ; Wakatsuki, Soichi ; Chan, Justin ; Capece, Mark C ; Chae, Hee-Don ; Capolicchio, Samanta ; Horikoshi, Naoki ; Butler, Tae-León

Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.

15 Nov 2018·Cancer ResearchQ1 · MEDICINE

CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia

Q1 · MEDICINE

Article

Author: Schrappe, Martin ; Cario, Gunnar ; Jeong, Johan ; Cleary, Michael L. ; Morgens, David W. ; Duyster, Justus ; Lin, Chiou-Hong ; Bassik, Michael C. ; Jeng, Edwin E. ; Xiao, Xiangshu ; Zhu, Li ; Han, Kyuho ; Wong, Stephen Hon Kit ; Sakamoto, Kathleen M. ; Wei, Michael C. ; Weng, Ziming ; Duque-Afonso, Jesús ; Chae, Hee-Don

AbstractDasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.

01 Jun 2018·CytotechnologyQ4 · BIOLOGY

Synergistic tumor suppression by a Perilla frutescens-derived methoxyflavanone and anti-cancer tyrosine kinase inhibitors in A549 human lung adenocarcinoma

Q4 · BIOLOGY

Article

Author: Kawamoto, Seiji ; Baba, Kenji ; Ono, Kazuhisa ; Hirakawa, Noriko ; Fujimura, Takashi ; Kamei, Rikiya ; Abd El-Hafeez, Amer Ali

Anti-cancer tyrosine kinase inhibitors (TKIs) are effective in many types of cancers including non-small cell lung cancer, while appearance of TKI-resistant tumors suggests a need for the development of their potentiation strategies. We have previously shown that a methoxyflavanone derivative from the Asian medicinal herb Perilla frutescens (Perilla-derived methoxyflavanone; PDMF) shows a prominent anti-tumor activity against A549 human lung adenocarcinoma. Here we show that PDMF and anti-cancer TKIs (nilotinib, bosutinib, dasatinib, and ponatinib) synergistically suppress proliferation of A549 cells. Flow cytometric analysis indicated that co-stimulation with nilotinib (4 μM) and PDMF induced G₂/M cell cycle arrest in low PDMF doses (10-50 μM), whereas this combination triggered de novo G₁ arrest in higher PDMF dosages (50-125 μM). We also found that co-administration with nilotinib and PDMF significantly suppressed in vivo tumorigenicity of A549 cells in athymic nude mice.

100 Deals associated with XX-650-23

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Discovery	United States	University of California, Los Angeles	-

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