Tag: M.W=300-350

Vannam, Raghu published the artcileTargeted degradation of the enhancer lysine acetyltransferases CBP and p300, Application of tert-Butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate, the publication is Cell Chemical Biology (2021), 28(4), 503-514.e12, database is CAplus and MEDLINE.

The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. Small mol. inhibitors that target some of these domains have been developed; however, they cannot completely ablate p300/CBP function in cells. Here we describe a chem. degrader of p300/CBP, dCBP-1. Leveraging structures of ligand-bound p300/CBP domains, we use in silico modeling of ternary complex formation with the E3 ubiquitin ligase cereblon to enable degrader design. dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drives MYC oncogene expression. As an efficient degrader of this unique class of acetyltransferases, dCBP-1 is a useful tool alongside domain inhibitors for dissecting the mechanism by which these factors coordinate enhancer activity in normal and diseased cells.

Cell Chemical Biology published new progress about 1936429-06-9. 1936429-06-9 belongs to pyrazoles-derivatives, auxiliary class Pyrazoles, name is tert-Butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate, and the molecular formula is C14H10O4, Application of tert-Butyl 3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Gummadi, Venkateshwar Rao published the artcileDiscovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode, Related Products of pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry Letters (2013), 23(17), 4911-4918, database is CAplus and MEDLINE.

We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7m and 7n demonstrate excellent potencies in biochem. and cellular assays. X-ray crystal structure of one of the compounds (7k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.

Bioorganic & Medicinal Chemistry Letters published new progress about 1415825-05-6. 1415825-05-6 belongs to pyrazoles-derivatives, auxiliary class Boronic acid and ester,Boronic Acids,Boronate Esters, name is 1-(2-Fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and the molecular formula is C16H20BFN2O2, Related Products of pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Katoh, Taisuke published the artcileDiscovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors, Category: pyrazoles-derivatives, the publication is Bioorganic & Medicinal Chemistry (2016), 24(11), 2466-2475, database is CAplus and MEDLINE.

A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the Et moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.

Bioorganic & Medicinal Chemistry published new progress about 1009071-34-4. 1009071-34-4 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Amide,Boronate Esters,Boronic Acids,Boronic acid and ester, name is tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, and the molecular formula is C15H25BN2O4, Category: pyrazoles-derivatives.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Kurasawa, Osamu published the artcileIdentification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones, Quality Control of 1009071-34-4, the publication is Bioorganic & Medicinal Chemistry (2017), 25(7), 2133-2147, database is CAplus and MEDLINE.

Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking anal. of a known inhibitor with Cdc7 homol. model. The pharmacophore model provided a min. structural motif of Cdc7 inhibitor, by which preliminary medicinal chem. efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a, c, e. Furthermore, the high selectivity of 14c, e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.

Bioorganic & Medicinal Chemistry published new progress about 1009071-34-4. 1009071-34-4 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Amide,Boronate Esters,Boronic Acids,Boronic acid and ester, name is tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, and the molecular formula is C15H25BN2O4, Quality Control of 1009071-34-4.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Kurasawa, Osamu published the artcileDiscovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent, Safety of tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, the publication is Journal of Medicinal Chemistry (2020), 63(3), 1084-1104, database is CAplus and MEDLINE.

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analog I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chem. efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclin. candidate. In this paper, the design, synthesis, and biol. evaluation of this series of compounds will be presented.

Journal of Medicinal Chemistry published new progress about 1009071-34-4. 1009071-34-4 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Amide,Boronate Esters,Boronic Acids,Boronic acid and ester, name is tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, and the molecular formula is C15H25BN2O4, Safety of tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Kurasawa, Osamu published the artcileDiscovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent, Safety of tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, the publication is Journal of Medicinal Chemistry (2020), 63(3), 1084-1104, database is CAplus and MEDLINE.

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analog I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chem. efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclin. candidate. In this paper, the design, synthesis, and biol. evaluation of this series of compounds will be presented.

Journal of Medicinal Chemistry published new progress about 1009071-34-4. 1009071-34-4 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Amide,Boronate Esters,Boronic Acids,Boronic acid and ester, name is tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, and the molecular formula is C15H25BN2O4, Safety of tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics

Kurasawa, Osamu published the artcile2-Aminomethylthieno[3,2-d]pyrimidin-4(3H)-ones bearing 3-methylpyrazole hinge binding moiety: Highly potent, selective, and time-dependent inhibitors of Cdc7 kinase, Quality Control of 1009071-34-4, the publication is Bioorganic & Medicinal Chemistry (2017), 25(14), 3658-3670, database is CAplus and MEDLINE.

To increase the success rate for developing new Cdc7 inhibitors for cancer therapy, the authors explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b (2-methyl-6-(pyridin-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one) with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity. Indeed, a pyrrolidinylmethyl derivative 10c (6-(3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl) thieno[3,2-d]pyrimidin-4(3H)-one) was a potent Cdc7 inhibitor (IC₅₀ = 0.70 nM) with high selectivity (Cdk2/Cdc7鈮?4,000, ROCK1/Cdc7=200). It should be noted that 10c exhibited significant time-dependent Cdc7 inhibition with slow dissociation kinetics, cellular pharmacodynamic (PD) effects, and COLO205 growth inhibition. Addnl., mol. basis of high kinase selectivity of 10c is discussed by using the protein structures of Cdc7 and Cdk2.

Bioorganic & Medicinal Chemistry published new progress about 1009071-34-4. 1009071-34-4 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Amide,Boronate Esters,Boronic Acids,Boronic acid and ester, name is tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, and the molecular formula is C15H25BN2O4, Quality Control of 1009071-34-4.

Referemce:
https://en.wikipedia.org/wiki/Pyrazole,
Pyrazoles – an overview | ScienceDirect Topics