rs4;11

MD-224 is a highly potent and efficacious MDM2 degrader based on the proteolysistargeting chimera (PROTAC) concept,and as a new class of anticancer agent.

USP7-IN-4(USP7 inhibitor ALM4) is a non-competitive, potent and selective inhibitor of USP7 (ubiquitin-specific protease 7) with an IC50 = 6 nM, up-regulates p53 and p21, down-regulates MDM2, increases the level of ubiquitination of MDM2, and exhibits anti-proliferative activity in a variety of cancer cell lines, with an EC50 = 2.0 nM in RS4;11 (acute lymphoblastic leukemia cell line) .

PROTAC BET degrader-2 is a highly potent degrader of Bromodomain and Extra-Terminal (BET) proteins, with an IC50 of 9.6 nM.

Lenalidomide-C4-NH2 hydrochloride is a Cereblon ligand derived from Lenalidomide. It serves as a recruiting agent for the CRBN protein. The compound, known as PROTAC (Compound 24), can be formed by linking Lenalidomide-C4-NH2 hydrochloride to the ligand for the protein. It exhibits inhibitory effects with IC50s of 0.98 nM and 13.7 nM against the growth of RS4;11 and MOLM-13 acute leukemia cell lines, respectively[1].

KT-253 is a p53 stabilizer and a PROTAC degrader of MDM2 (DC50=0.4 nM). It inhibits the proliferation of cancer cells RS4;11 with an IC50 of 0.3 nM, induces cell cycle arrest in the G2/M phase, and triggers apoptosis. In mouse models, KT-253 demonstrates antitumor activity. (Pink: ligand for target protein MDM2 ligand 4; Black: linker; Blue: ligand for E3 ligase cereblon)

MD-4251 is an orally active MDM2 PROTAC degrader. It potently degrades MDM2 in RS4;11 cells (DC50: 0.2 nM) and activates p53. MD-4251 exhibits strong antiproliferative activity against acute leukemia cells with wild-type p53, but shows limited efficacy in mutant cells. In RS4;11 xenograft mouse models, MD-4251 induces complete tumor regression.

USP7-IN-18 (Compound X21) serves as a novel USP7 inhibitor by directly suppressing enzyme activity and modulating downstream pathways, including the newly identified PCLAF target. At concentrations of 0.25-1 μM for 24 hours, it exhibits inhibitory effects. USP7-IN-18 effectively reduces proliferation in leukemia (RS4;11) and colon cancer (MC38/CT26.WT) cells at 0.01-100 μM over 72 hours. It demonstrates high selectivity for USP7 at 2.5 μM within 0.5 hours, surpassing eight other deubiquitinating enzymes. SPR analysis shows that at 1.95-2000 nM for 3 minutes, the compound binds the catalytic domain of USP7 with a KD value of 4.9 μM.

Mesutoclax (ICP-248) (Compound 5) is a selective BCL-2 inhibitor with an IC50 of 1.54 nM, demonstrating weak activity against BCL-XL (IC50: >1000 nM). It inhibits the viability of RS4;11 cells with an IC50 of 2.75 nM and can be utilized in cancer research.

AS-99 is a first-in-class, potent, and selective ASH1L histone methyltransferase inhibitor (IC50= 0.79 μM, Kd= 0.89 μM) with anti-leukemic activity, blocking cell proliferation, inducing apoptosis and differentiation, downregulating MLL fusion target genes, and reducing the leukemia burden in vivo[1].

AS-99 TFA is a first-in-class, potent, and selective ASH1L histone methyltransferase inhibitor (IC50= 0.79 μM, Kd= 0.89 μM) with anti-leukemic activity. It blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo[1].

USP7-IN-9, a potent inhibitor of ubiquitin-specific protease 7 (USP7) with an IC50 of 40.8 nM, effectively induces apoptosis and arrests cell progression at the G0/G1 and S phases in RS4;11 cells. It decreases the protein levels of oncoproteins MDM2 and DNMT1 while enhancing the levels of tumor suppressors p53 and p21.

Bcl-2-IN-4, an orally active and selective inhibitor of Bcl-2, demonstrates potent efficacy with an IC50 value of 1.5 nM and exhibits more than 200-fold selectivity over Bcl-xL (IC50 of 411 nM). Additionally, it effectively inhibits the proliferation of RS4;11 cells, achieving an IC50 of 2.7 nM.

Bcl-2-IN-5 is a potent BCL-2 inhibitor with inhibitory concentrations (IC50) of 0.12 nM, 0.14 nM, and 0.22 nM against wild type Bcl-2, Bcl-2 D103Y, and Bcl-2 G101V, respectively. It also suppresses cell growth in Bcl 2-G101V knock-in [RS4;11] cells, with IC50 values of 0.2 nM and 0.44 nM.

U7D-1, a groundbreaking and selective ubiquitin-specific protease 7 (USP7) PROTAC degrader, exhibits a DC50 value of 33 nM in RS4;11 cells, demonstrating its potent anticancer properties. Furthermore, U7D-1 effectively induces apoptosis in Jeko-1 cells [1].

AD4 is an artemisinin-derived proteolysis targeting chimera that selectively degrades PCLAF protein with subnanomolar potency in RS4;11 leukemia cells,AD4 leads to activation of the p21/Rb signaling axis, robust anti-tumor activity, and significantly prolonged survival in RS4;11 xenograft NOD/SCID mouse models, demonstrating both in vitro and in vivo therapeutic efficacy.

XM-U-14 is a selective PROTAC USP7 degrader that induces the degradation of USP7 in the RS4;11 cell line with a DC50 of 0.74 nM. This compound elevates the levels of p53 and p21, and significantly inhibits the growth of acute lymphoblastic leukemia (ALL) cells, with IC50 values of 0.5 nM in RS4;11 cells and 8.3 nM in Reh cells. Moreover, XM-U-14 induces apoptosis and cell cycle arrest, and effectively inhibits tumor growth.