title: Suprafenacine, an indazole-hydrazide agent, targets cancer cells through microtubule destabilization.
abstract: Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule--4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK-mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Bo-Hwa
authors.initials: BH
authors.lastname: Choi
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Souvik
authors.initials: S
authors.lastname: Chattopadhaya
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Le Nguyen
authors.initials: le N
authors.lastname: Thanh
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Quoc Toan
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Chuan Bian
authors.initials: CB
authors.lastname: Lim
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Amaravadhi
authors.initials: A
authors.lastname: Harikishore
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Ravi Prakash Reddy
authors.initials: RP
authors.lastname: Nanga
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Nagakumar
authors.initials: N
authors.lastname: Bharatham
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D003078:Colchicine / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007191:Indazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D007191:Indazoles; D054852:Small Molecule Libraries; C000598895:suprafenacine; D003078:Colchicine