Molecular Glues

Thalidomide (Thalomid) is a synthetic derivative of glutamic acid (alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory, anti-inflammatory and anti-angiogenic properties.

Lenalidomide (CC-5013) is an immunomodulator with oral activity. Lenalidomide is a ligand for the ubiquitin E3 ligase cereblon (CRBN), which selectively ubiquitinates and degrades two lymphoid transcription factors, IKZF1 and IKZF3, via the CRBN-CRL4 ubiquitin ligase, and is commonly used in the synthesis of PROTAC products.

Pomalidomide (CC-4047) is an anti-angiogenic and immunomodulatory agent. Pomalidomide is a ligand for the ubiquitin E3 ligase cereblon (CRBN) and is commonly used in the synthesis of PROTAC products.

dCeMM1, a RBM39 glue degrader, re-directs the activity of the CRL4DCAF15 ligase and decreases RBM39 expression levels in WT KBM7 cells.

PT-179 is a novel IMiD derivative, a molecular gel.

Dicyclanil is an insect growth regulator with a chemical structure similar to that of cyclopromazine.

Lenalidomide hemihydrate is a derivative of Thalidomide, an orally active immunomodulator that acts as a molecular gel. It is a ligand for the ubiquitin E3 ligase cereblon, which selectively ubiquitinates and degrades two lymphoid transcription factors, IKZF1 and IKZF3, via the CRBN-CRL4 ubiquitin ligase.

FPFT-2216 is a molecular gel that degrades IKZF6, IKZF1, DE1D, and CK3α.FPFT-2216 has potential antitumor activity and can be used to study diseases of the immune system.FPFT-2216 is a molecular gel that degrades IKZF6, IKZF1, DE1D, and CK3α.

Antitumor agent-100 hydrochloride (compound A6), serving as both an apoptosis inducer and molecular glue, exhibits superior anti-tumor activity [1].

Naphthyridine carbamate dimer (NCD) acts as a molecular glue for DNA, facilitating specific structural alterations within targeted functional DNA sequences to modulate their activity [1].

dCeMM2 is a glue degrader. dCeMM2 prompts an interaction of CDK12-cyclin K with a CRL4B ligase complex, leading to the ubiquitination and degradation of cyclin K.

VAV1 degrader-3 is an orally active and efficient VAV1 molecular glue degrader that reduces immune cell activation, proliferation, and cytokine production, useful for studying inflammation and autoimmune diseases.

VAV1 degrader-2 (Example 176) is a molecular gel degrader (DC50=4.41 nM) that targets VAV 1 for the study of inflammatory and autoimmune diseases.

dWIZ-1 ((rac)-dWIZ-1) is a potent WIZ molecular gel degrader that recruits WIZ (ZF7) to the cereblon thereby inducing degradation and thus induction of haemoglobin fetalis (HbF) in erythroblasts, which can be used to study sickle cell disease (SCD).

BMS-986449 is a CELMoD-type molecular gel that remodels the function of regulatory T cells (Treg) and enhances their anti-tumor immune responses by directing the E3 ubiquitin ligase, Cereblon, to target the degradation of IKZF2 (Helios) and IKZF4 (Eos). BMS-986449 has potential application in the study of advanced solid tumors.

CQ627 is a molecular glue that targets the degradation of RIOK2. It effectively recruits the E3 ubiquitin ligase RNF126, inducing the proteasomal degradation of RIOK2 via the ubiquitin-proteasome system (UPS) in MOLT4 leukemia cell lines, with a DC50 value of 410 nM. Additionally, CQ627 induces apoptosis in a dose-dependent manner in these cells, blocking the cell cycle at the G2 M phase, and exhibits antiproliferative activity across various cancer cell lines. It also demonstrates in vivo anticancer activity in MOLT4 xenograft mouse models.

GR-14-3-3 stabilizer-1 (compound 10) is a molecular glue stabilizer designed for the creation of a molecular adhesive that targets glucocorticoid receptors (GR), thereby inhibiting the interaction between GR and 14-3-3 proteins.

ChREBPα 14-3-3 regulator-1 (Compound 43) is a selective molecular glue that stabilizes the interaction between carbohydrate response element-binding protein (ChREBP) and 14-3-3 proteins, with an EC50 of 3.8 μM. It effectively safeguards β cells from glucolipotoxicity, preserving cell function and making it relevant for type 2 diabetes research.

IPS-06061 is an orally active molecular glue that forms a ternary complex with CRBN and KRASG12D, capable of degrading KRAS G12D, with a DC50 of less than 500 nM.

HGC652 is a molecular glue that targets the E3 ubiquitin ligase TRIM21, facilitating the formation of a ternary complex between TRIM21 and NUP98, which induces the degradation of NUP155 and nuclear pore complex proteins, ultimately leading to cell death. HGC652 inhibits the proliferation of various cancer cells, with its antiproliferative activity depending on the expression level of TRIM21.

QXG-6442 is a molecular glue degrader targeting CK1α, demonstrating a degradation potency with a DC50 of 5.7 nM and a Dmax of 90%. In the MOLM-14 cell line, QXG-6442 induces antiproliferative effects.

XYD049 (compound 7d) is a CRBN-type molecular glue targeting GSPT1, with a DC50 of 19 nM, used for researching MYC-driven castration-resistant prostate cancer (CRPC). It effectively inhibits the growth of 22Rv1 cells (IC50 = 7 nM) and exhibits antitumor efficacy in vivo. XYD049 downregulates CRPC-associated oncogenes in 22Rv1 cells, including AR, AR-v7, PSA, and c-Myc. XYD049 comprises a molecular glue linker (black part) NH2-C5-NH-Boc, a CRBN-type E3 ligase ligand (blue part) Thalidomide 4-fluoride, and a target protein ligand (red part) GSPT1 ligand-1, with the E3 ligase ligand + linker forming the conjugate E3 Ligase Ligand-linker Conjugate 158.

LYG-409 is an orally active GSPT1 degrader. It demonstrates exceptional in vivo anti-tumor activity against acute myeloid leukemia and prostate cancer, with tumor growth inhibition rates (TGI) of 94.34% and 104.49%, respectively. LYG-409 inhibits KG-1 cells by degrading GSPT1, with an IC50 of 9.50 nM and a DC50 of 7.87 nM in vitro.

dGEM3 is a molecular glue degrader targeting GEMIN3 (a component of the survival of motor neuron complex). It is applicable in research on diseases related to abnormal protein regulation, such as cancer and neurodegenerative disorders.