eRF3a/GSPT1 Degrader

CC-885, a cereblon (CRBN) modulator, acts as a molecular glue degrader targeting GSPT1 with a K_d of 350 nM. CC-885 binds to CRBN to alter the substrate specificity of the CRL4 E3 ligase, promoting the ubiquitination and proteasomal degradation of GSPT1, BNIP3L, PLK1, CDK4, IKZF1/3, GSPT2, WIZ, CHD7, GOLM1, CK1α and ETS1. CC-885 induces apoptosis, cell cycle arrest, transcriptional downregulation and antiproliferation in cancer cells. CC-885 is applicable to research related to relapsed/refractory acute myeloid leukemia, MYC-driven tumors, metastatic castration-resistant prostate cancer, multiple myeloma, hepatocellular carcinoma, glioblastoma, VHL-deficient clear cell renal cell carcinoma and non-small cell lung cancer.

Eragidomide (CC-90009) is a GSPT1 Molecular Glue degrader. Eragidomide exhibits antiproliferative and pro-apoptotic (apoptosis) activities against acute myeloid leukemia cells. Eragidomide recruits the CRL4CRBN E3 ubiquitin ligase complex to selectively target GSPT1 for ubiquitination and proteasomal degradation. Eragidomide reduces leukemia cell engraftment and eliminates leukemia stem cells. Eragidomide promotes the activation of the GCN1/GCN2/ATF4 pathway and the integrated stress response pathway, inhibits global protein translation, promotes preferential translation of ATF4, and induces the accumulation of ATF4, CHOP and ATF3. The response to Eragidomide is regulated by the ILF2/ILF3 heterodimer complex, the mTOR signaling pathway and the integrated stress response. Eragidomide can be used in research related to acute myeloid leukemia and relapsed/refractory acute myeloid leukemia.

MRT-2359 is an orally active and selective GSPT1 molecular glue degrader, with a DC₅₀ of 5 nM. MRT-2359 induces CRBN/GSPT1 ternary complex formation to drive CRBN- and degron-dependent proteasomal GSPT1 degradation, with selectivity for wild-type GSPT1 over the GSPT1^G575N mutant. MRT-2359 disrupts protein translation, induces ribosome stalling, downregulates MYC family proteins and their transcriptional output, reduces proliferation, and induces apoptosis in cancer cells. MRT-2359 can be used for the research of non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), neuroendocrine lung cancer, high grade neuroendocrine cancers, diffuse large B-cell lymphoma, prostate cancer, and MYC-driven solid tumors.

SJ6986 is an orally active GSPT1/2 molecular glue degrader, with a DC₅₀ of 9.7 nM at 4 h and 2.1 nM at 24 h for GSPT1 degradation in MV4-11 cells. SJ6986 recruits GSPT1/2 to the CRBN E3 ligase complex, inducing ubiquitination and proteasomal degradation of GSPT1/2. SJ6986 triggers activation of the integrated stress response pathway and apoptosis downstream of GSPT1 degradation. SJ6986 serves as a chemical probe for investigating the functions of GSPT1/GSPT2 in vitro and in vivo. SJ6986 can be used for research on acute leukemia and medulloblastoma.

GT19630 is an orally active c-Myc PROTAC targeted degrader based on the cereblon E3 ubiquitin ligase, with an IC₅₀ of 1.5 nM against human c-Myc. GT19630 mediates the degradation of MYC, GSPT1, GSPT2, CK1 alpha, N-Myc, B7-H3 and XIAP, and disrupts the MYC-GSPT1 synergistic regulatory feedback loop. GT19630 inhibits cell proliferation, blocks S-phase progression of the cell cycle, promotes cell apoptosis, reduces cell migration capacity, induces integrated stress response, and blocks oxidative phosphorylation by inhibiting the TCA cycle. GT19630 can be used in the research of Myc-driven hematological cancers, small cell lung cancer, breast cancer, TP53-mutant cancers, and venetoclax-resistant cancers.

SJ988497 is a PROTAC degrader targeting JAK2. SJ988497 induces the proteasomal degradation of CRBN-mediated JAK2, JAK1, JAK3, GSPT1, and IKZF1, and functions as a CRBN neosubstrate for GSPT1. SJ988497 retains binding affinity for the kinase domain of JAK2. SJ988497 can be used in studies related to cancers such as crlf2-rearranged acute lymphoblastic leukemia.

MDEG-541 is a PROTAC degrader targeting MYC, GSPT1/2 and PLK1. MDEG-541 induces degradation via proteasome- and ubiquitin-dependent pathways. MDEG-541 exhibits anti-tumor activity in gastrointestinal cancer cells and patient-derived organoids. MDEG-541 can be used for the research of gastrointestinal cancer.

GBD-9 is a degrader based on the E3 ubiquitin ligase CRBN that targets BTK and the G1 to S phase transition protein GSPT1. GBD-9 has both PROTAC and molecular glue properties by inducing ubiquitination and proteasomal degradation of target proteins. GBD-9 can efficiently degrade wild-type and mutant BTK (such as C481S mutation) and GSPT1. GBD-9 significantly inhibits tumor cell proliferation by inducing G1 phase arrest in cancer cells, downregulating anti-apoptotic proteins (BCL-2, MCL-1) and activating Caspase-3 to induce apoptosis. GBD-9 is mainly used in the research of hematological tumors such as diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML).

ZXH-1-161 is a potent CRBN modulator that selectively induces the degradation of GSPT1 in a CRBN-dependent manner. ZXH-1-161 can inhibit the proliferation of multiple myeloma cells and exhibits antitumor activity.

MG-277, a molecular glue degrader, effectively induces degradation of a translation termination factor based on Cereblon E3 ligand, GSPT1, with a DC₅₀ of 1.3 nM. MG-277 potently inhibits tumor cell growth in a p53-independent manner, with IC₅₀s of 3.5 nM for RS4;11 cells and 3.4 nM for p53 mutant RS4;11/IRMI-2 cells, respectively. Anticancer activity.

LYG-409 is a highly potent, selective, and orally active GSPT1 molecular glue degrader. LYG-409 induces GSPT1 degradation in KG-1 cells with a DC₅₀ of 7.87 nM. LYG-409 binds to Cereblon with an IC₅₀ of 191 nM, promotes the formation of the CRBN-GSPT1 ternary complex, and induces proteasome-dependent degradation of GSPT1. LYG-409 exhibits broad antiproliferative and GSPT1-degrading activities in a variety of hematologic and solid tumor cells. LYG-409 can be used for studies related to GSPT1-targeted protein degradation, acute myeloid leukemia, and prostate cancer.

Sontigidomide is a protein molecular glue degrader that can effectively degrade IKZF1/3 and GSPT1 proteins. Sontigidomide can be used to study inflammatory and immune system diseases. GSPT1/IKZF1/3 Molecular Glue Degrader

SJPYT-195 is a molecular glue degrader targeting GSPT1, with a DC₅₀ of 310 nM. SJPYT-195 mediates CRBN-dependent and proteasome-dependent degradation of GSPT1 by forming a stable ternary complex with CRBN and GSPT1. As a secondary effect of GSPT1 degradation, SJPYT-195 induces a decrease in PXR protein levels. SJPYT-195 is applicable to research related to acute myeloid leukemia.

GSPT1 degrader-19 is a molecular glue degrader targeting GSPT1, IKZF1 and IKZF3, with DC₅₀ values of 0.88 nM, 11.54 nM and 13.84 nM, respectively, in MM.1S multiple myeloma cells. GSPT1 degrader-19 induces cereblon (CRBN)-dependent ubiquitination and proteasomal degradation of IKZF1, IKZF3, GSPT1 and GSPT2, and also reduces ZFP91 protein levels via a CRBN-dependent pathway. GSPT1 degrader-19 exerts antiproliferative effects on cancer cells, induces global proteomic changes including downregulation of novel substrates, and exhibits activity against multiple myeloma and leukemia cell lines. GSPT1 degrader-19 can be used in research related to multiple myeloma and leukemia.

KMG-1068 is a molecular glue degrader that induces proteasomal degradation of GSPT1 and GSPT2 with DC₅₀ values of 126.7 nM and 42.2 nM, respectively. KMG-1068 binds to the C-terminal IMiD-binding site of CRBN, forms ternary complexes with GSPT1 and GSPT2, and mediates proteasomal degradation of target proteins via the CRL4 ubiquitination pathway. KMG-1068 is applicable to research related to acute myeloid leukemia.

MI-389 is a potent menin-MLL interaction inhibitor (IC₅₀=25 nM) and a CRBN-recruiting, GSPT1-targeted PROTAC degrader. MI-389 upregulates myeloid differentiation-related genes that are lowly expressed in primitive hematopoietic progenitor cells, thereby inducing myeloid differentiation phenotypic changes in MLL-rearranged leukemia cells. MI-389 competitively blocks the MG-H1-RAGE interaction to interfere with the AGEs-RAGE pathway, thus alleviating AGEs-induced HUVEC injury. MI-389 can be used in studies related to MLL-rearranged acute leukemia.

ABS-752 hydrochloride is an orally active prodrug targeting CRBN-modulating molecular glue with selectivity in protein degradation. ABS-752 hydrochloride preferentially degrades GSPT1 and induces cytotoxicity through this degradation, while it also degrades NEK7, SALL4 and CK1α, with weaker degradation potency against CK1α. As a prodrug, ABS-752 hydrochloride requires metabolic activation to ABT-002 to form the active complex; VAP-1 mediates its conversion to an aldehyde intermediate. ABS-752 hydrochloride induces cell death, reduces cell viability, and exhibits antitumor activity, leading to regression and inhibition of tumor growth. ABS-752 hydrochloride shows no cytotoxicity in primary human hepatocytes. ABS-752 hydrochloride can be used in the research of hepatocellular carcinoma.

AN5777 is a GSPT1 Molecular glue degrader with a DC₅₀ of less than 10 μM. AN5777 degrades GSPT1 in a CRBN-dependent manner via the ubiquitin-proteasome system. AN5777 induces G1 phase arrest and Apoptosis in cancer cells. AN5777 is applicable to research related to acute myeloid leukemia, multiple myeloma, and chronic myeloid leukemia.

XYD049 is a CRBN-based molecular glue degrader targeting GSPT1, with a DC₅₀ of 19 nM. XYD049 mediates the formation of a ternary complex between CRBN and GSPT1, thereby triggering CRBN- and proteasome-dependent degradation of GSPT1. By degrading GSPT1, XYD049 downregulates castration-resistant prostate cancer (CRPC)-related oncogenes, including BCL2, CDK2, E2F3, EGFR, HSP90B1, TMPRSS2, AR, AR-V7, PSA and c-Myc. XYD049 inhibits cancer cell growth and suppresses tumor growth in mice. XYD049 can be used for research on castration-resistant prostate cancer. XYD049 consists of a linker (black part) NH2-C5-NH-Boc (HY-W004710), a CRBN-based E3 ligase ligand (blue part) Thalidomide 4-fluoride (HY-41547), and a target protein ligand (red part) GSPT1 ligand-1 (HY-170821), among which the E3 ligase ligand plus linker forms the conjugate E3 Ligase Ligand-linker Conjugate 158 (HY-170822).

GSPT1 degrader-15 (Compound Lib-B-15O) is a potent and highly selective GSPT1 molecular gel degrader, with a DC₅₀ of 154 nM. GSPT1 degrader-15 has almost no effect on the expression of other proteins. GSPT1 degrader-15 exhibits significant anti-proliferative activity against leukemia cells and lymphoma cells. GSPT1 degrader-15 can be used in leukemia and lymphoma research.