Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

01 Dec 2021·Journal of Experimental & Clinical Cancer ResearchQ1 · MEDICINE

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting

Q1 · MEDICINE

ArticleOA

Author: Parma, Beatrice ; Napoli, Francesca ; Zhang, Shuman ; Schwab, Annemarie ; Gollavilli, Paradesi Naidu ; Marschall, Sabine ; Schrøder, Henrik Daa ; Volante, Marco ; Wurdak, Heiko ; Ceppi, Paolo ; Siddiqui, Aarif ; Ramesh, Vignesh ; Stemmler, Marc ; Pinna, Luisa ; Mielenz, Dirk ; Urbanczyk, Sophia ; Pilarsky, Christian

AbstractBackgroundThe identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures.MethodsGene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9.ResultsWe show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients’ prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B.ConclusionsThese results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.

15 Aug 2018·Science Translational MedicineQ1 · MEDICINE

KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice

Q1 · MEDICINE

Article

Author: Patel, Anjana ; Allison, Simon J. ; Abbosh, Christopher ; Polson, Euan S. ; Ballereau, Stephane ; Roberts, Lee D. ; Short, Susan C. ; Droop, Alastair ; Shao, Hao ; Holding, Andrew N. ; Zhu, Shoutian ; Gestwicki, Jason E. ; Mathew, Ryan K. ; Ross, Edith M. ; Beard, Hester A. ; Chumas, Paul ; Williams, Jennifer ; Bon, Robin S. ; Kuchler, Verena B. ; Chuntharpursat-Bon, Eulashini ; Wurdak, Heiko ; da Silva, Bárbara ; Davies, Adam J. ; Markowetz, Florian ; Griffiths, Hollie B.S. ; Lorger, Mihaela

Modulation of energy metabolism with the small-molecule KHS101 promoted tumor-selective death of human glioblastoma cells and reduced tumor growth in mice.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	GB	University of Leeds	-
Central nervous system injury	Discovery	US	Genomics Institute Of The Novartis Research Foundation	-
Central nervous system injury	Discovery	US	The Scripps Research Institute	-
Central Nervous System Neoplasms	Discovery	US	The Scripps Research Institute	-
Central Nervous System Neoplasms	Discovery	US	Genomics Institute Of The Novartis Research Foundation	-
Neurodegenerative Diseases	Discovery	US	Genomics Institute Of The Novartis Research Foundation	-
Neurodegenerative Diseases	Discovery	US	The Scripps Research Institute	-

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