SOS1 PROTAC 9d   Click here for help

GtoPdb Ligand ID: 12069

Compound class: Synthetic organic
Comment: This compound (9d) is a SOS1-directed PROTAC [2]. It is a hybrid molecule combining a VHL ligand and a SOS1 agonist (from [1]). Although the SOS1-interacting part of this PROTAC is an agonist it mediates efficient SOS1 protein degradation. In vitro 9d provides antiproliferative activity against human cancer cells with various KRAS mutations, and it inhibits tumour growth in a xenograft mouse model.
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

✖
Canonical SMILES O[C@@H]1C[C@H](N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCN1CCN(CC1)c1cc(Cl)cc2c1nc(n2Cc1cc(C)c(c(c1)C)F)N1CC2(C1)CNC2)C(=O)N[C@H](c1ccc(cc1)c1scnc1C)C
Isomeric SMILES O=C(CCCCCCCCN1CCN(c2c3nc(n(c3cc(Cl)c2)Cc2cc(C)c(c(c2)C)F)N2CC3(C2)CNC3)CC1)N[C@H](C(=O)N1C[C@@H](C[C@H]1C(=O)N[C@H](c1ccc(cc1)c1c(ncs1)C)C)O)C(C)(C)C
InChI InChI=1S/C57H76ClFN10O4S/c1-36-24-40(25-37(2)49(36)59)29-69-46-27-43(58)26-45(50(46)64-55(69)67-33-57(34-67)31-60-32-57)66-22-20-65(21-23-66)19-13-11-9-8-10-12-14-48(71)63-52(56(5,6)7)54(73)68-30-44(70)28-47(68)53(72)62-38(3)41-15-17-42(18-16-41)51-39(4)61-35-74-51/h15-18,24-27,35,38,44,47,52,60,70H,8-14,19-23,28-34H2,1-7H3,(H,62,72)(H,63,71)/t38-,44+,47-,52+/m0/s1
InChI Key AZBRWXRYNYEDKG-VWELVXIZSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
9d degrades SOS1 protein by 92.5% at 1 μM [2], We obtained the binding affinity (Kd) value for the SOS1 agonist component of this PROTAC from Hodges et al. (2018) [1]. This value may be slightly altered by inclusion in the larger PROTAC molecule.
Selectivity at other protein targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
SOS Ras/Rac guanine nucleotide exchange factor 1 Hs Agonist Agonist 7.4 pKd - 1
⤷ pKd 7.4 (Kd 4.4x10-8 M) [1]