CST626 is a PROTAC degrader targeting IAP, with DC50 values of 0.7 nM, 2.4 nM and 6.2 nM against XIAP, cIAP1 and cIAP2, respectively. This compound recruits the VHL E3 ubiquitin ligase to form a heterotrimeric complex, thereby inducing ubiquitination and proteasomal degradation of the target proteins. CST626 also exhibits certain degrading activity against VHL30 and VHL19. CST626 inhibits the proliferation and induces apoptosis of various hematologic tumor cell lines, and its anti-tumor effect is further enhanced when used in combination with TNF-α. CST626 can be used in research related to multiple myeloma, acute myeloid leukemia and diffuse large B-cell lymphoma [1] [2]. (Pink: IAP and XIAP ligand; Blue: VHL ligand; Black: linker).
In Vitro, CST626 (0.0001-1 μM; 16 h) potently induces pan-IAP degradation in MM.1S cells with DC50 values of 0.7 nM (XIAP), 2.4 nM (cIAP1), and 6.2 nM (cIAP2), and also degrades VHL isoforms[1]. CST626 (0.1 μM; 3-6 h) induces complete degradation of cIAP1, cIAP2, and XIAP in MM.1S cells within 3 h at 0.1 μM, with maximal VHL30 degradation observed at 6 h[1]. CST626 (1 μM; single exposure, followed by incubation up to 72 h post-washout) mediates long-lasting pan-IAP degradation in MM.1S cells for up to 72 h after a single 1 μM exposure, while VHL isoform levels recover more quickly[1]. CST626-induced IAP degradation in MM.1S cells relies on the functional ubiquitin-proteasome system[1]. CST626 (0.1 μM; 3 h) selectively degrades cIAP1 and XIAP in MM.1S cells at 0.1 μM after 3 h, with no significant off-target proteome-wide effects[1]. CST626 (0.0016-10 μM; 96 h) potently inhibits viability of multiple hematological cancer cell lines under TNF-α-challenged conditions, with IC50 values ranging from 0.0016 μM (SUDHL6) to 2.54 μM (RPMI-8226), and shows superior activity compared to IAP antagonists in select cell lines[1]. Combination of VenAza with CST626 (100 nM) significantly increases cytotoxicity in TP53+/+ and TP53-/R248Q MOLM-13 AML cells compared to VenAza or CST626 alone[2]. CST626 (100-200 nM) induces apoptosis in TP53+/+, TP53-/R248Q, and TP53-/- MOLM-13 AML cells, with greater apoptosis observed at the 200 nM concentration compared to 100 nM[2].
References:
[1]. Ng YLD, et al. Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins. Journal of medicinal chemistry. 2023 Apr 13;66(7):4703-4733.
[2]. Mamdouh AM, et al. Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia. bioRxiv [Preprint]. 2025 May 22:2025.05.17.654633.
In Vitro, CST626 (0.0001-1 μM; 16 h) potently induces pan-IAP degradation in MM.1S cells with DC50 values of 0.7 nM (XIAP), 2.4 nM (cIAP1), and 6.2 nM (cIAP2), and also degrades VHL isoforms[1]. CST626 (0.1 μM; 3-6 h) induces complete degradation of cIAP1, cIAP2, and XIAP in MM.1S cells within 3 h at 0.1 μM, with maximal VHL30 degradation observed at 6 h[1]. CST626 (1 μM; single exposure, followed by incubation up to 72 h post-washout) mediates long-lasting pan-IAP degradation in MM.1S cells for up to 72 h after a single 1 μM exposure, while VHL isoform levels recover more quickly[1]. CST626-induced IAP degradation in MM.1S cells relies on the functional ubiquitin-proteasome system[1]. CST626 (0.1 μM; 3 h) selectively degrades cIAP1 and XIAP in MM.1S cells at 0.1 μM after 3 h, with no significant off-target proteome-wide effects[1]. CST626 (0.0016-10 μM; 96 h) potently inhibits viability of multiple hematological cancer cell lines under TNF-α-challenged conditions, with IC50 values ranging from 0.0016 μM (SUDHL6) to 2.54 μM (RPMI-8226), and shows superior activity compared to IAP antagonists in select cell lines[1]. Combination of VenAza with CST626 (100 nM) significantly increases cytotoxicity in TP53+/+ and TP53-/R248Q MOLM-13 AML cells compared to VenAza or CST626 alone[2]. CST626 (100-200 nM) induces apoptosis in TP53+/+, TP53-/R248Q, and TP53-/- MOLM-13 AML cells, with greater apoptosis observed at the 200 nM concentration compared to 100 nM[2].
References:
[1]. Ng YLD, et al. Heterobifunctional Ligase Recruiters Enable pan-Degradation of Inhibitor of Apoptosis Proteins. Journal of medicinal chemistry. 2023 Apr 13;66(7):4703-4733.
[2]. Mamdouh AM, et al. Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia. bioRxiv [Preprint]. 2025 May 22:2025.05.17.654633.