Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers

Abstract

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRAS G12D -and G12V -mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.

Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve

“…Investigation of the linker length revealed that compound 12d ( PIK5-12d ) with 4 −CH 2 – in the middle of the linker showed the best PIKfyve degradative activity with the degradation rates of 97 and 91% at 0.1 and 1 μM, respectively. Interestingly, the substitution of the VHL ligand in PIK5-12d with a more potent version resulted in compound 13a with decreased activity . We also synthesized compound 12dN ( PIK5-12dN) as a negative control by using the inactive isomer of the VHL ligand, and it turned out to have no degradative activity against PIKfyve as expected (Table ).…”

“…Interestingly, the substitution of the VHL ligand in PIK5-12d with a more potent version resulted in compound 13a with decreased activity. 24 We also synthesized compound 12dN (PIK5-12dN) as a negative control by using the inactive isomer of the VHL ligand, 25 PIKfyve in the preliminary screening. To further characterize this compound, we treated VCaP cells with PIK5-12d with different concentrations for 24 h. The results showed that compound PIK5-12d dose-dependently induced PIKfyve degradation with a DC 50 value of 1.48 nM and a D max value of 97.9% (Figure 3A).…”

Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo

“…50 The selective SOS1 degrader S6, which recruits the E3 ligase VHL, significantly inhibited tumor growth of KRAS G12D and KRAS G12 V mutant xenografts in mice. 51 It may have poor physicochemical properties due to the VHL ligand. There is still an unmet need for more effective efficient SOS1 degraders for patients bearing KRAS mutant tumors.…”

“…SOS1 agonist-based degrader S5 could induce SOS1 degradation in multi-KRAS-driven cancer cells, but the antitumor activities were weak with IC 50 of 0.525 μM against H358 cells and SOS1 DC 50 of 0.098 μM . The selective SOS1 degrader S6 , which recruits the E3 ligase VHL, significantly inhibited tumor growth of KRAS G12D and KRAS G12 V mutant xenografts in mice . It may have poor physicochemical properties due to the VHL ligand.…”

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor

“…Son-of-sevenless homologue 1 (SOS1), as the primary guanine nucleotide exchange factors (GEFs), plays a key role in regulating RAS activity by catalyzing the exchange of KRAS from inactive GDP-bound to active GTP-bound form. , To date, the reported small molecules targeting SOS1 mainly include inhibitors, agonists, and degraders (Figure D). − Inhibitors, such as BAY-293, BI-3406, and BI-1701963 block RAS activation by disrupting of the RAS–SOS1 interaction. Among them, BI-1701963 has entered phase I clinical trial as a monotherapy or in combination with the MEK inhibitor trametinib (NCT04111458).…”