Antiproliferative

Thailanstatin A is an ultra-potent inhibitor of eukaryotic RNA splicing (IC50 = 650 nM). It inhibits multiple cancer cell lines via non-covalent binding to the SF3b subunit of the U2 snRNA subcomplex of the spliceosome, displaying low-nM to sub-nM IC50s. Thailanstatin A, as a payload for ADCs, is conjugated to the lysines on trastuzumab, yielding linker-less ADC.

BSJ-4-116 is a highly potent and selective CDK12 degrader (PROTAC) with an IC50 of 6 nM. It downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation).

PROTAC METTL3 degrader 1 (Compound KH12) is a VHL-based degrader of METTL3, demonstrating a DC50 of 220 nM in MOLM-13 cells. This compound inhibits the METTL3 14 complex with an IC50 of 341 nM and exhibits antiproliferative activity against AML cells.

PROTAC SMARCA2-degrader-36 (compound 38) is an SMARCA2 degrader that achieves a 99% degradation rate at 100 nM in H929 cells. It possesses antiproliferative activity and is used in cancer research.

PROTAC SMARCA2 degrader-26 (compound 45) is an effective degrader of SMARCA2 using the PROTAC technology. It induces degradation of SMARCA2 and SMARCA4 in VCaP cells, with degradation percentages of 94% and 57%, respectively. Additionally, PROTAC SMARCA2 degrader-26 demonstrates antiproliferative activity.

CQ-16 is an orally active small molecule drug conjugate (SMDC) that targets prostate-specific membrane antigen (PSMA). It exhibits high selectivity in its antiproliferative activity between PSMA-positive and PSMA-negative prostate cells. Additionally, CQ-16 possesses PARP inhibitory activity (IC50=1 nM).

CPD-10 is a potent bifunctional PROTAC degrader targeting CCND1 and CDK4 and exhibits antiproliferative effects. It induces apoptosis and reduces the protein expression of Cyclin D1, Cyclin D3, CDK4, and P-Rb(5807 811) in a dose-dependent manner.

CSI86 is a PROTAC degrader targeting MYC, exhibiting antiproliferative activity (IC50: 13-18 μM).

CPD-39 is an efficacious and orally active bifunctional PROTAC degrader targeting both CCND1 and CDK4. It exhibits antiproliferative effects.

BTX-6654 is a cereblon-based bifunctional SOS1 PROTAC degrader. This compound exhibits antiproliferative activity against cells with various KRAS mutations by reducing the expression of downstream signaling markers pERK and pS6.

YB-3-17 is a bifunctional molecule that can inhibit mTOR with an IC50 of 0.22 nM or degrade the G1 to S phase transition 1 gene (GSPT1) through the PROTAC mechanism, with a DC50 of 5 nM. It exhibits antiproliferative activity at nanomolar concentrations in various glioblastoma cell lines. Additionally, YB-3-17 shows antitumor activity in mouse models. (Pink: ligand for target protein; Black: linker; Blue: ligand for E3 ligase Cereblon)

PROTACSMARCA2 4 degrader-36 (Compound 29) is a potent dual degrader targeting SMARCA2 and SMARCA4, exhibiting DC50 values of 0.22 nM and 0.85 nM, respectively. Additionally, PROTACSMARCA2 4 degrader-36 demonstrates antiproliferative activity.

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.

DP-15 acts as a degrader of GSPT1 and BRD4, with DC50 values of 5.25 nM and 0.48 nM, respectively. This compound exhibits antiproliferative activity in AML and NHL cells, showing IC50 values in the nanomolar range, induces G1 phase cell cycle arrest, and triggers apoptosis in MOLM13 cells. Additionally, DP-15 demonstrates anti-leukemic properties in the MOLM-13 xenograft mouse model. [Pink: ligand for target protein JQ-1 carboxylic acid; Black: linker; Blue: ligand for E3 ligaseCereblonThalidomide-5-OH]

E3 Ligase Ligand-linker Conjugate 170 (Compound I) demonstrates antiproliferative activity in non-Hodgkin's lymphoma SU-DHL-4 cells, with an IC50 of less than 0.2 μM. This conjugate is composed of an E3 ligase ligand and a linker, making it suitable for use in PROTAC synthesis.

P1D-34 is a Pin1 PROTAC degrader with a DC50 value of 177 nM. It downregulates Pin1 substrate proteins, including Cyclin D1, Rb, Mcl-1, Akt, and c-Myc. Additionally, P1D-34 exhibits antiproliferative activity across various acute myeloid leukemia (AML) cell lines and induces DNA damage and apoptosis by generating reactive oxygen species (ROS).

L1BC8 (compound 13a) is a BRD4 PROTAC degrader with anticancer properties. It also serves as a drug-linker conjugate for ADC, suitable for ADC synthesis. The resulting BRD4 degrader antibody conjugates demonstrate potent antigen-dependent BRD4 degradation and antiproliferative activity in cellular assays.

PROTACKDM4 degrader-1 (Compound 11) is a proteolysis-targeting chimera (PROTAC) degrader specifically designed for KDM4. It effectively degrades KDM4A-C while sparing KDM4D. In esophageal cancer cells, PROTACKDM4 degrader-1 demonstrates strong antiproliferative activity, inducing apoptosis and cell cycle arrest, and inhibits lysine demethylation of histone H3.

CW-2 is a PARP1 PROTAC degrader known for its potent antiproliferative effects against MDA-MB-231 cells (IC50 = 0.72 μM) and cisplatin-resistant cells (A549/CDDP: IC50 = 3.52 μM). It exhibits synergistic antitumor activity and enhanced membrane permeability. CW-2 exerts its antitumor effects by inducing DNA damage, disrupting DNA repair, and triggering mitochondrial-dependent apoptosis (apoptosis).

dBRD9 HCl is a PROTAC composed of the BRD9 inhibitor BI 7273 conjugated to the cereblon E3 ligase ligand pomalidomide . dBRD9 HCl is a potent and selective degrader of BRD9 (IC50 = 56.6 nM in MOLM-13 cells). dBRD9 HCl does not degrade BRD4 or BRD7 at concentrations up to 5 μM. dBRD9 HCl displays antiproliferative effects in human AML cell lines.

MIF degrader MD13 is involved in protein-protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active siteMIF degrader MD13. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF-directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.

PROTAC BRD9-binding moiety 5, a selective binder of BRD9 with an IC50 value of 4.20 μM, is utilized in PROTAC synthesis and exhibits antiproliferative activity against cancer cells [1].