2. Academic Validation
  3. Anti-glioma effects of 2-aminothiophene-3-carboxamide derivatives, ANO1 channel blockers

Anti-glioma effects of 2-aminothiophene-3-carboxamide derivatives, ANO1 channel blockers

  • Eur J Med Chem. 2020 Dec 15;208:112688. doi: 10.1016/j.ejmech.2020.112688.
Seung-Hye Choi 1,  SeongShick Ryu 1,  Kyoungmi Sim 2,  Chiman Song 3,  Injae Shin 4,  Seong-Seop Kim 2,  Young-Sun Lee 2,  Jae-Yong Park 2,  Taebo Sim 5
Affiliations

Affiliations

  • 1 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
  • 2 School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea.
  • 3 Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
  • 4 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 5 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: tbsim@yuhs.ac.
PMID: 32906067 DOI: 10.1016/j.ejmech.2020.112688
Abstract

Anoctamin1 (ANO1), a calcium-activated chloride ion channel (CaCC), is associated with various physiological functions including Cancer progression and metastasis/invasion. ANO1 has been considered as a promising target for Cancer therapeutics as ANO1 is over-expressed in a variety of cancers including glioblastoma (GBM) and inhibition of ANO1 has been reported to suppress cell proliferation, migration and invasion in GBM. GBM is one of the most common and aggressive cancers with poor prognosis with median survival for 15 months. Lack of effective treatment options against GBM emphasizes urgent necessity of effective GBM therapeutics. In an effort to discover potent and selective ANO1 inhibitors capable of inhibiting GBM cells, we have designed and synthesized a series of new 2-aminothiophene-3-carboxamide derivatives and performed SAR studies using both fluorescent cellular membrane potential assay and whole-cell patch-clamp recording. We observed that among these substances, 9c and 10q strongly suppress ANO1 channel activities and possess remarkable selectivity over ANO2. Unique structural feature of 10q, a cyclopentane-fused thiophene-3-carboxamide derivative, is the presence of benzoylthiourea functionality which dramatically contributes to activity. Both 9c and 10q suppress more strongly proliferation of GBM cells than four reference compounds including 3, Ani-9 and are also capable of inhibiting much more strongly colony formation than reference compounds in both 2D colony formation assay and 3D soft agar assay using U251 glioma cells. In addition, 9c and 10q suppress far more strongly migration/invasion of GBM cells than reference compounds. We, for the first time, found that the combination of ANO1 inhibitor (9c or 3) and temozolomide (TMZ) brings about remarkable synergistic effects in suppressing proliferation of GBM cells. Our study may provide an insight into designing selective and potent ANO1 inhibitors aiming at GBM treatment.

Keywords

2-Aminothiophene-3-carboxamides; ANO1 chloride ion channel; ANO1 inhibitors; Combination of TMZ and ANO1 inhibitor; Glioblastoma (GBM).

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