CQ627 is a molecular glue degrader of right open reading frame kinase 2 ( RIOK2 ). CQ627 inhibits the ATPase activity of RIOK2 in MOLT-4 cells with an IC50 of 98 nM. By recruiting the E3 ubiquitin ligase RNF126, CQ627 promotes RIOK2 ubiquitination and induces its degradation via the ubiquitin-proteasome system (UPS), while inhibiting RIOK2-dependent mTOR / AKT signaling, suppressing cancer cell proliferation, and inducing G2/M cell cycle arrest and apoptosis. CQ627 can be used in studies related to RIOK2-targeted protein degradation and leukemia [1].
In Vivo, CQ627 (10 mg/kg; i.p.; administered consecutively for 2 days followed by a 4-day drug holiday, for a total of 3 cycles) inhibits tumor growth in a female CB17-SCID mouse MOLT-4 xenograft model, with a TGI of 18.6%. No significant body weight loss is observed during the experiment; the RIOK2 protein level in tumor tissues decreases significantly at 4 h after the final administration[1].
In Vitro, CQ627 (compound 9s) (12 h) induces dose-dependent degradation of RIOK2 in MOLT-4 cells, with a DC50 of 0.41 μM and a Dmax of 83.4%[1]. CQ627 (1 μM; 4-24 h) reduces RIOK2 protein levels in MOLT-4 cells in a time-dependent manner; a significant reduction is observed at 12 h, with the maximum degradation rate reaching 94.8% at 24 h[1]. CQ627 (1 μM; 12 h) induces RIOK2 degradation in MOLT-4 cells; pretreatment with MG-132 (1 μM; 2 h) or MLN4924 (20 μM; 2 h) restores RIOK2 protein levels, indicating that CQ627-induced RIOK2 degradation depends on the proteasome and Cullin-RING E3 ubiquitin ligase system[1]. CQ627 (67.5-1000 nM; 12 h) inhibits the RIOK2-dependent mTOR/AKT signaling pathway in MOLT-4 cells, and suppresses the activation of mTOR and AKT at 500 nM[1]. CQ627 (1 μM; 12 h) induces RIOK2 degradation in MOLT-4 cells; the RNF126 ligand JP-2-196 (5 μM; 2 h pre-treatment) reverses this degradation effect, while CQ627 increases the ubiquitination level of RIOK2, indicating that CQ627 induces RIOK2 degradation via the ubiquitin-proteasome system (UPS) by recruiting the E3 ubiquitin ligase RNF126[1]. CQ627 (72 h) inhibits the proliferation of various tumor cells, with IC50 values of 0.13, 0.34 and 0.12 μM against MOLT-4, HL-60 and OCILY3 cells, respectively. Moreover, its antiproliferative activity in various tumor cells is approximately 3- to 10-fold higher than that of CQ211[1]. CQ627 (0.5 nM-10 μM; 2 h) inhibits RIOK2 ATPase activity in the ADP-Glo assay, with an IC50 of 0.098 μM[1]. CQ627 (900 nM; 24 h) induces 39.60% G2/M cell cycle arrest in MOLT-4 cells, and induces G2/M phase arrest in a dose-dependent manner[1]. CQ627 (900 nM; 48 h) induces 57.11% apoptosis in MOLT-4 cells and triggers apoptosis in a dose-dependent manner[1].
References:
[1]. Ma H, et al. Discovery of the first examples of right open reading frame kinase 2 (RIOK2) molecular glue degraders. European journal of medicinal chemistry. 2025 Feb 05;283:117166.
In Vivo, CQ627 (10 mg/kg; i.p.; administered consecutively for 2 days followed by a 4-day drug holiday, for a total of 3 cycles) inhibits tumor growth in a female CB17-SCID mouse MOLT-4 xenograft model, with a TGI of 18.6%. No significant body weight loss is observed during the experiment; the RIOK2 protein level in tumor tissues decreases significantly at 4 h after the final administration[1].
In Vitro, CQ627 (compound 9s) (12 h) induces dose-dependent degradation of RIOK2 in MOLT-4 cells, with a DC50 of 0.41 μM and a Dmax of 83.4%[1]. CQ627 (1 μM; 4-24 h) reduces RIOK2 protein levels in MOLT-4 cells in a time-dependent manner; a significant reduction is observed at 12 h, with the maximum degradation rate reaching 94.8% at 24 h[1]. CQ627 (1 μM; 12 h) induces RIOK2 degradation in MOLT-4 cells; pretreatment with MG-132 (1 μM; 2 h) or MLN4924 (20 μM; 2 h) restores RIOK2 protein levels, indicating that CQ627-induced RIOK2 degradation depends on the proteasome and Cullin-RING E3 ubiquitin ligase system[1]. CQ627 (67.5-1000 nM; 12 h) inhibits the RIOK2-dependent mTOR/AKT signaling pathway in MOLT-4 cells, and suppresses the activation of mTOR and AKT at 500 nM[1]. CQ627 (1 μM; 12 h) induces RIOK2 degradation in MOLT-4 cells; the RNF126 ligand JP-2-196 (5 μM; 2 h pre-treatment) reverses this degradation effect, while CQ627 increases the ubiquitination level of RIOK2, indicating that CQ627 induces RIOK2 degradation via the ubiquitin-proteasome system (UPS) by recruiting the E3 ubiquitin ligase RNF126[1]. CQ627 (72 h) inhibits the proliferation of various tumor cells, with IC50 values of 0.13, 0.34 and 0.12 μM against MOLT-4, HL-60 and OCILY3 cells, respectively. Moreover, its antiproliferative activity in various tumor cells is approximately 3- to 10-fold higher than that of CQ211[1]. CQ627 (0.5 nM-10 μM; 2 h) inhibits RIOK2 ATPase activity in the ADP-Glo assay, with an IC50 of 0.098 μM[1]. CQ627 (900 nM; 24 h) induces 39.60% G2/M cell cycle arrest in MOLT-4 cells, and induces G2/M phase arrest in a dose-dependent manner[1]. CQ627 (900 nM; 48 h) induces 57.11% apoptosis in MOLT-4 cells and triggers apoptosis in a dose-dependent manner[1].
References:
[1]. Ma H, et al. Discovery of the first examples of right open reading frame kinase 2 (RIOK2) molecular glue degraders. European journal of medicinal chemistry. 2025 Feb 05;283:117166.