molecular glue

Mezigdomide (CC-92480) is a potent, novel, selective and active cereblon E3 ubiquitin ligase modulator (CELMoD) that acts as a molecular glue. Mezigdomide has anti-myeloma activity. [1]

N-Boc-4-pentyne-1-amine is an alkyl chain-based PROTAC linker compound used in the synthesis of PROTAC MG-277 [1].

MG-277 is a molecular glue compound transformed from PROTAC degradation agent, MG-277 potently inhibits tumor cell growth in a p53-independent manner.

(R)-CR8 trihydrochloride (CR8, (R)-Isomer trihydrochloride) is a CDK1 2 5 7 9 inhibitor that acts as a molecular glue degrader with neuroprotective activity and induces apoptosis.

KB02-JQ1 is a potent and specific proteolysis targeting chimera (PROTAC) that specifically degrades BRD4, acting as a molecular glue. It does not degrade BRD2 or BRD3. The mechanism of action involves covalent modification of the E3 ligase DCAF16, thereby promoting BRD4 degradation. Importantly, KB02-JQ1 demonstrates enhanced stability and durability in facilitating protein degradation within biological systems. The compound forms a complex with the ubiquitin E3 ligase ligand KB02 through a linker, resulting in the formation of KB02-JQ1[1].

KB02-SLF is a PROTAC-based nuclear FKBP12 degrader, also known as a molecular glue, that facilitates the degradation of nuclear FKBP12 by covalently modifying DCAF16, an E3 ligase. SLF acts as a linker, binding to the ubiquitin E3 ligase ligand KB02, thus forming KB02-SLF[1] and enhancing the longevity of protein degradation in biological systems.

QS-57 is a PROTAC that targets BRD4 and can also function as a molecular glue for 14-3-3.

SJ46411-Br is an orally effective CK1α molecular glue (Molecular Glue) degrader. It binds with CRL2^KLHDC2 to facilitate the formation of a cooperative homoselective ternary complex. Furthermore, SJ46411-Br is coupled with the BET ligand JQ1 through a PROTAC linker, enabling the synthesis of corresponding PROTACs.

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.

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.

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.

Lenalidomide hydrochloride (CC-5013 hydrochloride), a Thalidomide derivative, functions as molecular glue and serves as an orally active immunomodulator. As a ligand for the ubiquitin E3 ligase cereblon (CRBN), it facilitates the selective ubiquitination and degradation of the lymphoid transcription factors IKZF1 and IKZF3 through the CRBN-CRL4 ubiquitin ligase. Specifically, Lenalidomide hydrochloride inhibits the growth of mature B-cell lymphomas, including multiple myeloma, and promotes IL-2 release from T cells [1] [2].

LSN3160440 is an allosteric modulator of GLP-1R that functions as a protein-protein interaction (PPI) stabilizer or molecular glue, aiding in the binding of inactive GLP-1 (9-36) NH2 to GLP-1R, thereby enhancing receptor activation and potential therapeutic effects [1] [2].

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

GBD-9, a dual-mechanism degrader, effectively promotes the degradation of BTK and GSPT1 through recruitment of E3 ligase cereblon (CRBN). As a PROTAC molecule, GBD-9 induces BTK degradation, while also acting as a molecular glue for GSPT1 degradation, demonstrating potent inhibition of cancer cell growth [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].

Lenalidomide (sodium), a Thalidomide derivative, serves as a molecular glue and an orally active immunomodulator. It acts as a cereblon (CRBN) ligand and triggers selective ubiquitination and subsequent degradation of the lymphoid transcription factors IKZF1 and IKZF3 via the CRBN-CRL4 ubiquitin ligase. Echoing its specificity, Lenalidomide (sodium) inhibits the proliferation of mature B-cell lymphomas, notably multiple myeloma, and promotes IL-2 secretion from T cells [1] [2].

KT-333 ammonium (Compound A) acts as a molecular glue that targets and promotes the degradation of the STAT3 protein through the ubiquitin-proteasome system. This compound achieves selective degradation by binding simultaneously to the STAT3 protein and the E3 ubiquitin ligase von Hippel-Lindau protein (VHL). It exhibits strong selectivity and efficacy in degrading STAT3, possessing notable antitumor properties. KT-333 ammonium is particularly useful for research on hematologic malignancies, including large granular lymphocytic leukemia (LGL-L), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL) [1].

PROTACGSPT1 degrader-2 (compound A) acts as a molecular glue for GSPT1, achieving degradation efficiencies exceeding 95%. Meanwhile, GSPT1 degrader-8 exhibits inhibitory effects on HL-60 cells, demonstrating an IC50 of 10 nM.

BRD9 Degrader-3 (compound B20) is a molecular glue for BRD9 with a DC50 of less than 1.25 nM.