About: ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells

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About: ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells
Creator	Amin, Shantu Narayan, Satya Ramisetti, Srinivasa Singh, Parvesh Singh-Pillay, Ashona Jaiswal, Aruna Law, Brian Sharma, A Sharma, Arun
topic	covid:5393fcedd64337c827b2580a6d4e6371fdd26258#this
Source	Elsevier; Medline; PMC
abstract	Abstract Despite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOX-resistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased γH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.
has issue date	2019-01-01(xsd:dateTime)
bibo:doi	10.1016/j.ejmech.2018.10.052
bibo:pmid	30384048
has license	els-covid
sha1sum (hex)	5393fcedd64337c827b2580a6d4e6371fdd26258
schema:url	https://doi.org/10.1016/j.ejmech.2018.10.052
resource representing a document's title	ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells
has PubMed Central identifier	PMC7115410
has PubMed identifier	30384048
schema:publication	European Journal of Medicinal Chemistry
resource representing a document's body	covid:5393fcedd64337c827b2580a6d4e6371fdd26258#body_text
is http://vocab.deri.ie/void#inDataset of	proxy:http/ns.inria.fr/covid19/5393fcedd64337c827b2580a6d4e6371fdd26258
is schema:about of	named entity 'therapeutic' named entity 'optimally' named entity 'CRC' named entity 'CRC' named entity 'effective' named entity 'metastatic' named entity 'stem cells' named entity 'NEW' named entity 'GROWTH INHIBITION' named entity 'REDUCED' named entity 'SYNTHESIS' named entity 'PATIENT' named entity 'CAPACITY' named entity 'THERAPEUTIC' named entity 'OXALIPLATIN' named entity 'AGENT' named entity 'FORMATION' named entity 'MESENCHYMAL' named entity 'IN VIVO' named entity 'EPIDERMAL' named entity 'SPHERE' named entity 'COMPLEX' named entity 'MODELS' named entity 'ONE OF' named entity 'METASTATIC' named entity 'STABLE' named entity 'LEADS' named entity 'SMALL MOLECULE' named entity 'STEM CELLS' named entity 'TOXICITY' named entity 'CYTOTOXICITY' named entity 'INDIRECT EFFECT' named entity 'FOLFOX' named entity 'IN VITRO KINASE ASSAY' named entity 'STEM CELL' named entity 'INDUCED' named entity 'DID' named entity 'ASR352' named entity 'CRITICAL' named entity 'ACTIVITY' named entity 'CLINICAL' named entity 'CHK1' named entity 'RATES' named entity 'IN VITRO' named entity 'NOVEL' named entity 'RECENTLY' named entity 'EMT' named entity 'BULK' named entity 'PRESENT' named entity 'RESISTANT' named entity 'BENEFITS' named entity 'TRANSITION' named entity 'SHORT-TERM' named entity 'TREATMENT' named entity 'SIGNIFICANT' named entity 'MECHANISM' named entity 'CURE' named entity 'RESISTANCE' named entity 'RATIO' named entity 'HAVE' named entity 'ENHANCEMENT' named entity 'CASPASE 3' named entity 'MEDIATED' named entity '5-FLUOROURACIL' named entity 'CRC' named entity 'THE CELL' named entity 'PATIENTS' named entity 'STUDY' named entity 'BAX' named entity 'S PHASE' named entity 'HIGH'

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