2. Academic Validation
  3. Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo

Discovery of [1,2,4]triazolo[4,3-a]pyridines as potent Smoothened inhibitors targeting the Hedgehog pathway with improved antitumor activity in vivo

  • Bioorg Med Chem. 2020 Aug 15;28(16):115584. doi: 10.1016/j.bmc.2020.115584.
Nannan Tian 1,  Huanxian Wu 2,  Huiwu Zhang 2,  Danni Yang 2,  Lin Lv 2,  Zichao Yang 2,  Tingting Zhang 2,  Dongling Quan 2,  Lei Zhou 2,  Ying Xie 3,  Yimei Xu 4,  Ning Wei 5,  Jiajie Zhang 2,  Mian Chen 6,  John C Schmitz 7,  Yuanxin Tian 8,  Shaoyu Wu 9
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China.
  • 3 State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau, China.
  • 4 The Center for Disease Control and Prevention of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830002, China.
  • 5 Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford OX3 7LE, United Kingdom.
  • 7 Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 8 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 9 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 32690258 DOI: 10.1016/j.bmc.2020.115584
Abstract

Triple-negative breast Cancer (TNBC), a subset of breast cancers, have poorer survival than other breast Cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo Inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against Cancer cell lines in vitro, especially triple-negative breast Cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and Apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.

Keywords

Hedgehog pathway; Smoothened inhibitor; Triple-negative breast cancer.

Figures
Products