pralsetinib   Click here for help

GtoPdb Ligand ID: 10033

Synonyms: BLU-667 | BLU667 | Gavreto®
Approved drug
pralsetinib is an approved drug (FDA (2020))
Compound class: Synthetic organic
Comment: Pralsetinib (BLU-667) is a second-generation selective RET kinase inhibitor that is being developed by Blueprint Medicines [2]. It is Compound 130 in patent US20170121312A1 and our structure was drawn from the image therein [1]. Selective RET inhibitors have oncology potential for the treatment of solid tumours with oncogenic RET alterations (e.g. constitutively activating RET point mutations and RET gene rearrangements). They are expected to offer more effective anti-tumour efficacy in RET-driven tumours than the currently available multi-kinase inhibitors (such as cabozantinib and vandetanib) that have limited anti-RET activity, and which have exhibited poor therapeutic responses in this defined patient group.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 135.01
Molecular weight 533.27
XLogP 3.29
No. Lipinski's rules broken 0
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Canonical SMILES COC1(CCC(CC1)c1nc(C)cc(n1)Nc1n[nH]c(c1)C)C(=O)NC(c1ccc(nc1)n1ncc(c1)F)C
Isomeric SMILES CO[C@@]1(CC[C@@H](CC1)c1nc(C)cc(n1)Nc1n[nH]c(c1)C)C(=O)N[C@H](c1ccc(nc1)n1ncc(c1)F)C
InChI InChI=1S/C27H32FN9O2/c1-16-11-22(33-23-12-17(2)35-36-23)34-25(31-16)19-7-9-27(39-4,10-8-19)26(38)32-18(3)20-5-6-24(29-13-20)37-15-21(28)14-30-37/h5-6,11-15,18-19H,7-10H2,1-4H3,(H,32,38)(H2,31,33,34,35,36)/t18-,19-,27+/m0/s1
Bioactivity Comments
BLU-667 inhibits oncogenic RET proteins with known point mutations (V804L, V804M, M918T) and the CCDC6-RET fusion protein, with potencies equal to that at the wild type kinase [2]. BLU-667 inhibits RET autophosphorylation with a cellular IC50 of 5 nM and inhibits phosphorylation of downstream signalling partners (SHC, and ERK1/2) at concentrations at or below 10 nM in engineered cell lines. It is anti-proliferative in in vivo models with RET-driven tumours.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
ret proto-oncogene Primary target of this compound Hs Inhibitor Inhibition 9.4 pIC50 - 2
pIC50 9.4 (IC50 4x10-10 M) [2]
Description: In a biochemical assay.
kinase insert domain receptor Hs Inhibitor Inhibition 7.5 pIC50 - 2
pIC50 7.5 (IC50 3.5x10-8 M) [2]
Description: In a biochemical assay.