splice

(E/Z)-TG003 is a potent and ATP-competitive inhibitor of Cdc2-like kinase (Clk).

Telaglenastat (CB 839) (IC50 of 24 nM), an effective, specific, and oral inhibitor, which is bioavailable glutaminase, for recombinant human GAC.

Spliceostatin A is an anticancer agent and splicing inhibitor that inhibits the splicing mechanism of the spliceosome and inhibits mitotic clonal expansion and adipogenesis.Spliceostatin A induces cell cycle arrest in the G1 and G2/M phases, and induces apoptosis.

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.

AAK1-IN-1 (example 123) is an AAK1 (adaptor associated kinase 1) inhibitor with an IC50 of 2.2 nM. AAK1-IN-1 can be used for neurodegenerative diseases research[1]. Adaptor associated kinase 1 (AAK1) is a member of the Arkl/Prkl family of serine/threonine kinases. AAKl mRNA exists in two splice forms termed short and long. The long form predominates and is highly expressed in brain and heart. AAKl is enriched in synaptosomal preparations and is co-localized with endocytic structures in cultured cells. AAKl modulates clatherin coated endocytosis, a process that is important in synaptic vesicle recycling and receptor-mediated endocytosis[1]. [1]. Guanglin Luo, et al. Biaryl kinase inhibitors. WO2015153720A1.

2-Nitrobenzoic acid (o-Nitrobenzoic acid) is a antiproliferation agent. 2-Nitrobenzoic acid shows IC50 of 8.3 μM to jurkat cell line expressing T type calcium channel alpha 1H or its splice variant delta 25.

3’-Me Meayamycin D is a splice modulator that targets SF3B1 and PHF5A, affecting the pre-mRNA splicing process and downregulating MCL-1 expression. It inhibits the proliferation of cancer cell lines HCT116, SW48, A549, DMS53, and DMS114, with a GI50 range of 4.6-7.2 nM. In mice, it demonstrates good plasma stability with a half-life of 16 hours.

LO-4-25 is a covalent degrader targeting the androgen receptor (AR) and its splice variant AR-V7. It covalently binds to the E3 ubiquitin ligase CUL4 DCAF16, facilitating the ubiquitination of both AR and AR-V7, which are then recognized and degraded by the proteasome, leading to reduced protein levels of AR and AR-V7 in cells. LO-4-25 is promising for research on androgen-independent prostate cancer.

JJ-450 is a non-competitive antagonist that targets androgen receptors (AR), capable of inhibiting the transcriptional activity of both wild-type AR and mutant ARF876L. It demonstrates an IC50 of approximately 1-10 μM for suppressing AR transcriptional activity in PC3 cells and selectively binds to AR without competing for the ligand binding domain (LBD) with androgens. JJ-450 functions by inhibiting the nuclear translocation of AR and promoting the degradation of unbound ligand AR within the nucleus, thereby suppressing the transcriptional activity of AR and its splice variants, such as ARF876L. This compound can be utilized in studies of castration-resistant prostate cancer (CRPC) that are resistant to Enzalutamide (MDV3100).

1-Naphthyl phosphate potassium salt inhibits non-specific phosphatase.

Thailanstatin D, an analogue of Thailanstatin A, inhibits AR-V7 gene splicing by disrupting the interaction between U2AF65 and SAP155, hindering their binding to the polypyrimidine tract situated between the branch point and the 3' splice site. This compound displays potent tumor inhibitory properties in human castration-resistant prostate cancer (CRPC) xenografts, resulting in cellular apoptosis.

Telaglenastat (CB-839) hydrochloride is a first-in-class, reversible, and orally active inhibitor of glutaminase 1 (GLS1), selectively inhibiting the splice variants KGA (kidney-type glutaminase) and GAC (glutaminase C), as opposed to GLS2. Telaglenastat hydrochloride has an IC50 of 23 nM for endogenous glutaminase in mouse kidney and 28 nM in the brain, inducing autophagy and exhibiting antitumor activity.

Vercirnon (GSK1605786A) sodium is an orally bioavailable, selective, and potent CCR9 antagonist. It inhibits CCR9-mediated calcium mobilization and chemotaxis in Molt-4 cells with IC50 values of 5.4 nM and 3.4 nM, respectively. Vercirnon sodium demonstrates high selectivity, showing IC50 values exceeding 10 µM for CCR1-12 and CX3CR1-7 receptors. It also inhibits CCL25-directed chemotaxis in both CCR9 splice variants, CCR9A and CCR9B, with IC50 values of 2.8 nM and 2.6 nM, respectively.

Ar-V7-IN-1 (compound 47) is a potent inhibitor of Ar-V7, a genetic mRNA splice variant of the androgen receptor (AR) associated with resistance to AR-targeted therapy in patients with desmoplasia-resistant prostate cancer (mCRPC).

EPI-7170 is a ralaniten analogue and a potent antagonist of the androgen receptor N-terminal structural domain, blocking the transcriptional activity of the full-length AR (FL-AR) and AR splice variants (AR-Vs). EPI-7170 exhibits antitumor activity against enzalutamide resistant debulking resistant prostate cancer (CRPC).

Minnelide is an effective therapy against pancreatic cancer. Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants. Minnelide reduced tumor volume in multiple models of pancreatic cancer. Minnelide was a more effective drug against pancreatic cancer models. It effectively reduced tumor burden and tumor related morbidity in different unique but complementary mouse models. It reduced metastatic spread and increased survival in the different models as well.

PF-05089771 is a voltage-gated sodium channel 1.7 (Nav1.7) blocker (IC50: 11, 16, 33, and 20 nM for 5N11S, 5A11L, 5A11S, and 5A11L Nav1.7 splice variants, respectively). It is selective for Nav1.7 over Nav1.1-1.6 and 1.8 channels (IC50: 0.11-25 μM), L-typ

Tagarafdeg (CFT1946) is an orally available PROTAC degradator targeting mutant BRAF, capable of degrading BRAF V600E (Class I), G469A (Class II), G466V (type III) mutations, and the p61-BRAF V600E splice variant. It exhibits favourable selectivity within the proteome, including for wild-type BRAF and CRAF, and inhibits tumour cell proliferation.

BWA-522 is a small molecule, orally available protein-targeting chimera (PROTAC) that potentates the degradation of both full-length androgen receptor (AR-FL) and the AR-V7 splice variant. It specifically antagonizes the N-terminal domain (AR-NTD) of the androgen receptor (Androgen Receptor), prompting apoptosis in prostate cancer (PC) cells. In LNCaP xenograft models, BWA-522 demonstrated tumor growth inhibition (60 mg/kg, po; TGI=76%). The compound effectively reduced levels of AR-V7 and AR-FL by 77.3% at 1 μM and 72.0% at 5 μM, respectively, in VCaP and LNCaP cell lines [1].

(R)-SKBG-1 is an inhibitor of the RNA-binding protein NONO, with an EC50 value of 1.5 μM in 22Rv1 cells. (R)-SKBG-1 reduces mRNA and protein expression of the androgen receptor (AR) and its splice variants (AR-FL and AR-V7), inhibits the proliferation of various cancer cells, and affects the transcriptome and proteome of cancer cells.

Tyrosine kinase-IN-6 is a potent inhibitor of RON splice variants, exhibiting notable anticancer and antineoplastic effects [1].

NSC 194308 specifically enhances binding of the U2AF2 subunit to pre-mRNA, capturing early spliceosome assembly and killing leukaemia cell lines harbouring spliceosome mutations. It is applicable for studying pre-mRNA splicing dysregulation.

VNPP433-3β acts as a molecular glue degrader, targeting the androgen receptor (AR) and its splice variants (AR-Vs) as well as MAP kinase-interacting serine/threonine protein kinase Mnk1/2. It effectively inhibits the proliferation of cancer cells LNCaP, C4-2B, and CWR22Rv1, with GI50 values of 0.2, 0.3, and 0.31 μM, respectively. Additionally, VNPP433-3β shows favorable pharmacokinetics in CD-1 mice and suppresses tumor growth in the CWR22Rv1 xenograft mouse model.

Efzofitimod is a splice variant of histidyl-tRNA synthetase HARS1, created by fusing the immunomodulatory domain of HARS1 with the Fc segment of a human antibody. It targets neuropilin-2 (NRP2) and exhibits anti-inflammatory and immunomodulatory properties. Efzofitimod can downregulate both innate and adaptive immune responses in inflammatory disease conditions, helping to mitigate interstitial lung disease (ILD).