Synthesis of Pyrazolo[3,4-d]pyrimidines as Dual-targeted Inhibitors of HDAC1 and mTOR
     
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Synthesis of Pyrazolo[3,4-d]pyrimidines as Dual-targeted Inhibitors of HDAC1 and mTOR

Pyrazolo[3,4-d]pyrimidines - Perspective Inhibitors of HDAC1 and mTORHistone deacetylase 1 (HDAC1, GON-10, HD1, RPD3, RPD3L1, KDAC1) plays a key role in the regulation of eukaryotic gene expression. Numerous reports revealed that HDAC1 is considered one of the most promising targets for cancer therapy.

The mechanistic target of rapamycin (mTOR, mammalian target of rapamycin, FK506-binding protein 12-rapamycin-associated protein 1, FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS) is a serine/threonine protein kinase which regulates different cellular processes - cell growth, cell proliferation, cell survival, protein synthesis, autophagy, transcription and other. mTOR is overactivated in numerous tumors.

We offer the chemical optimization service - synthesis of two-target specific set of pyrazolo[3,4-d]pyrimidine derivatives as dual-targeted inhibitors of HDAC1 and mTOR. These novel compounds will be selected from a set of 2,000+ virtual pyrazolo[3,4-d]pyrimidines using our company’s proprietary molecular modeling platform, synthesized and provided for your biological projects.

This set of novel analogs will be synthesized exclusively upon your request.

This is referred to a paper from European Journal of Medicinal Chemistry* which showed that authors designed and synthesized pyrazolo[3,4-d]pyrimidines as dual-targeted inhibitors of HDAC1 and mTOR using pyrimidine-pyrazolyl pharmacophore to append HDAC recognition cap and hydroxamic acid as a zinc-binding motif. Compound 12l ((R)-N-(4-(1-(7-(Hydroxyamino)-7-oxoheptyl)-4-morpholino-1Hpyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-2-methylmorpholine-4-carboxamide) shows the optimal inhibition activities against both targets:

Pyrazolo[3,4-d]pyrimidines - Perspective Inhibitors of HDAC1 and mTOR

Compound 12l, HDAC1 IC50 = 0.19 nM, mTOR IC50 = 1.2 nM

 

Design and synthesis of compounds with both anti-HDAC1 and anti-mTOR effect is a promising direction in hematologic malignancies treatment.

 

* Yong Chen, Xue Yuan, Wanhua Zhang, Minghai Tang, Li Zheng, Fang Wang, Wei Yan, Shengyong Yang, Yuquan Wei, Jun He, Lijuan Chen. Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy. J. Med. Chem. 2019, Vol. 62(3), pp. 1577−1592, DOI: 10.1021/acs.jmedchem.8b01825.

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