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.
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2D Structure
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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
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]