78078-92-9

Upstream product

• 130-00-7 1,8-naphtholactam 
• 7797-81-1 N-hydroxy-1,8-naphthalenedicarboximide 
• 81-84-5 1,8-Naphthalic anhydride 
• 34599-42-3 6-nitrobenzindol-2(1H)-one 
• 50964-11-9 6-aminobenzindol-2(1H)-one 
• 5551-72-4 1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl 4-methylbenzenesulfonate 

Downstream Products

• 441745-43-3 AQ-390/10779040 
• 670266-26-9 C₁₇H₁₁ClN₂O₃S 
• 442534-82-9 C₁₇H₁₀Cl₂N₂O₃S 
• 443922-67-6 C₁₇H₁₁BrN₂O₃S 
• 794552-14-0 C₁₇H₁₁FN₂O₃S 
• 794552-13-9 C₁₇H₁₁FN₂O₃S 
• 1011889-00-1 C₁₈H₁₁F₃N₂O₃S 
• 62155-54-8 DC_BD₁₆₈ 
• 397281-20-8 AG-690/15438099 
• 791787-63-8 AG-690/10776061 
• 791787-59-2 C₁₉H₁₆N₂O₅S 
• 878617-35-7 C₁₉H₁₆N₂O₅S 

Relevant academic research and scientific papers

Discovery of Novel Phosphodiesterase-2A Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer’s disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 μM. Optimization of compound AQ-390/10779040 (IC50 = 4.6 μM) from the virtual screening, which holds a novel scaffold of benzo[cd]indol-2(1H)-one among PDE inhibitors, leads to discovery of a new compound LHB-8 with a significant improvement of inhibition (IC50 = 570 nM). The modeling studies demonstrated that LHB-8 formed an extra hydrogen bond with Asp808 and a hydrophobic interaction with Thr768, in addition to the common interactions with Gln859 and Phe862 of PDE2A. The novel scaffolds discovered in the present study can be used for rational design of PDE2A inhibitors with high affinity.

TARGETED BIFUNCTIONAL DEGRADERS

The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.

BIFUNCTIONAL SMALL MOLECULES TO TARGET THE SELECTIVE DEGRADATION OF CIRCULATING PROTEINS

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.

Design, synthesis and biological evaluation of benzo[cd]indol-2(1H)-ones derivatives as BRD4 inhibitors

Compound 1 bearing with benzo [cd]indol-2(1H)-one scaffold was identified as an effective BRD4 inhibitor through the AlphaScreen-based high-throughput screening and its high-resolution crystal structure with BRD4_BD1 protein. A series of 48 compounds were designed and synthesized by structural optimization on compound 1. All the compounds have been evaluated for their BRD4 inhibitory activities. The results showed that compounds 23, 24, 28 and 44 are the most potential ones with the IC50 values of 1.02 μM, 1.43 μM, 1.55 μM and 3.02 μM, respectively. According to their co-crystal structures in complex with BRD4_BD1 and the protein thermal shift assays, the binding modes were revealed that the additional indirect hydrogen bonds and hydrophobic interactions make such four compounds more active than 1 against BRD4. Furthermore, compounds 1, 23 and 44 were chosen to evaluate for their antiproliferative activities on the MLL-AF4-expression acute leukemia cell line (MV4-11), other cancer cell lines (MDA-MB-231, A549, 22Rv1) and the non-cancer cell lines (HUV-EC-C, MRC5, RPTEC). The results showed that these compounds exhibited good and selective inhibitory activities against MV4-11 cells with the IC50 values of 11.67 μM, 5.55 μM, and 11.54 μM, respectively, and could act on the cell proliferation by blocking cell cycle at G1 phase. They could markedly down-regulate the expressions of the c-Myc, Bcl-2 and CDK6 oncogenes in MV4-11 in the qRT-PCR and western blot studies, which further demonstrated that compound 1 and its derivatives could serve as a promising therapeutic strategy for MLL leukemia by targeting BRD4_BD1 protein.

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Design, synthesis and biological evaluation of naphthostyril derivatives as novel protein kinase FGFR1 inhibitors

New class of FGFR1 kinase inhibitors with naphthostyril heterocycle has been identified. A series of N-phenylnaphthostyril-1-sulfonamides has been synthesized and tested in vitro. It was revealed that the most active compound N-(4-hydroxyphenyl)naphthostyril-1- sulfonamide inhibited FGFR1 with IC50 of 2 μM. In our preliminary studies, N-phenylnaphthos-tyril- 1-sulfonamides demonstrated selectivity of FGFR1 inhibition and antiproliferative activity on cancer cell line. N-phenylnaphthostyril-1-sulfonamides have a good potential for further development as anticancer agents.

Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase

Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a Ki of 70 μM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π-π stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87.

Identification and characterization of novel inhibitors of mPTPB, an essential virulent phosphatase from mycobacterium tuberculosis

Mycobacterium protein tyrosine phosphatase B (mPTPB) is an essential virulence factor required for Mycobacterium tuberculosis (Mtb) survival in host macrophages. Consequently, mPTPB represents an exciting new target with a completely novel mechanism of action. We screened a library of 7500 compounds against mPTPB and identified several 2-oxo-1,2-dihydrobenzo[cd]indole-6- sulfonamide and piperazinyl-thiophenyl-ethyl-oxalamide derivatives as two distinct classes of mPTPB inhibitors. We showed that both classes of inhibitors are capable of blocking the mPTPB-mediated ERK1/2 inactivation. We further demonstrated that both classes of mPTPB inhibitors are effective in inhibiting the growth of Mtb in macrophages. Thus, improvement of the lead compounds may produce a novel class of anti-TB agents.