IRE1 agonists(Serine/threonine-protein kinase/endoribonuclease IRE1 agonists), PERK activators(eukaryotic translation initiation factor 2 alpha kinase 3 activators)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication-

Inactive Indication

Hepatocellular Carcinoma

Originator Organization

Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences

Active Organization-

Inactive Organization

Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC23H33ClN2O2

InChIKeyDBHCSAFZYROWFD-LPOZWGFCSA-N

CAS Registry1616292-40-0

100 Clinical Results associated with IMB-6G

100 Translational Medicine associated with IMB-6G

100 Patents (Medical) associated with IMB-6G

Literatures (Medical) associated with IMB-6G

09 Feb 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents

Q3 · MEDICINE

Article

Author: Deng, Hongbin ; Song, Danqing ; Bi, Chongwen ; Wang, Yanxiang ; Shao, Rongguang ; Fan, Tianyun ; Yang, Peng ; Zhang, Na ; Ye, Cheng

A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N'-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC₅₀ between 0.55 and 1.7 μM. The underlying mechanism of 6b against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound 6b is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.

26 Apr 2016·Oncotarget

IMB-6G, a novel N-substituted sophoridinic acid derivative, induces endoplasmic reticulum stress-mediated apoptosis via activation of IRE1α and PERK signaling

Article

Author: Bi, Chongwen ; Tang, Sheng ; Zhang, Na ; Deng, Hongbin ; Song, Danqing ; Liu, Lu ; Pang, Weiqiang ; Dou, Yueying

Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which precede induction of apoptosis. Further study showed IMB-6G activated IRE1α and PERK pathways but did not stimulated ATF6 pathway in HCC cells. Moreover, silencing of IRE1α dramatically abrogated IMB-6G-induced pro-apoptotic ASK1-JNK signaling. Importantly, interruption of CHOP rendered HCC cells sensitive to IMB-6G-induced apoptosis via inactivation of Bim, PUMA and Bax. Thus, the IRE1α-ASK1 and PERK-CHOP pathways may be a novel molecular mechanism of IMB-6G-induced apoptosis. Collectively, our study demonstrates that IMB-6G induces ER stress-mediated apoptosis by activating IRE1α and PERK pathways. Our findings provide a rationale for the potential application of IMB-6G in HCC therapy.

01 Jun 2014·European Journal of Medicinal ChemistryQ1 · MEDICINE

Novel N-substituted sophoridinol derivatives as anticancer agents

Q1 · MEDICINE

Article

Author: Deng, Hong-Bin ; Zhang, Cai-Xia ; Shao, Rong-Guang ; Bi, Chong-Wen ; Zhao, Wu-Li ; Tang, Sheng ; Wang, Zhen ; Song, Dan-Qing ; Li, Ying-Hong

Using sophoridine (1) as the lead compound, a series of new N-substituted sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. SAR analysis indicated that introduction of a chlorobenzyl on the 12-nitrogen atom of sophoridinol might significantly enhance the antiproliferative activity. Of the newly synthesized compounds, sophoridinol analogue 9k exhibited a potent effect against six human tumor cell lines (liver, colon, breast, lung, glioma and nasopharyngeal). The mode of action of 9k was to inhibit the DNA topoisomerase I activity, followed by the G0/G1 phase arrest. It also showed a moderate oral bioavailability and good safety in vivo. Therefore, compound 9k has been selected as a novel-scaffold lead for further structural optimizations or as a chemical probe for exploring anticancer pathways of this kinds of compounds.

100 Deals associated with IMB-6G

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Preclinical	China	Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences	18 Mar 2016

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