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
1. Hodges TR, Abbott JR, Little AJ, Sarkar D, Salovich JM, Howes JE, Akan DT, Sai J, Arnold AL, Browning C et al.. (2018)
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.
J Med Chem, 61 (19): 8875-8894. [PMID:30205005]
2. Zhou C, Fan Z, Zhou Z, Li Y, Cui R, Liu C, Zhou G, Diao X, Jiang H, Zheng M et al.. (2022)
Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations.
J Med Chem, 65 (5): 3923-3942. [PMID:35230841]