1428569-85-0

Basic information

• Product Name: GDC-0339
• Synonyms: 5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;EOS-60554
• CAS NO: 1428569-85-0
• Molecular Formula: C₂₀H₂₂F₃N₇OS
• Molecular Weight: 465.4951896
• EINECS: -0
• Mol File: 1428569-85-0.mol

Chemical Properties

• Appearance: /
• Density: 1.61±0.1 g/cm3(Predicted)
• PKA: 9.28±0.40(Predicted)
• CAS DataBase Reference: GDC-0339(CAS DataBase Reference)
• NIST Chemistry Reference: GDC-0339(1428569-85-0)
• EPA Substance Registry System: GDC-0339(1428569-85-0)

Safety Data

• Hazardous Substances Data: 1428569-85-0(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
GDC-0339 is used as an anticancer agent for the treatment of certain types of cancer, such as melanoma. It is used in combination with other targeted therapies to inhibit the growth and survival of cancer cells by blocking the activity of MEK proteins in the MAPK/ERK signaling pathway.
Used in Clinical Trials:
GDC-0339 is used as a subject of clinical trials to investigate its potential in treating other types of cancer. The trials aim to evaluate the safety, efficacy, and optimal dosing regimens of cobimetinib in combination with other targeted therapies for various cancer indications.
Used in Drug Development:
GDC-0339 serves as a lead compound in the development of new drugs targeting the MAPK/ERK signaling pathway. Researchers are exploring its potential for combination therapies and the development of next-generation MEK inhibitors with improved selectivity, potency, and reduced side effects.
Used in Cancer Research:
GDC-0339 is used as a research tool to study the role of the MAPK/ERK signaling pathway in cancer development and progression. It helps researchers understand the molecular mechanisms underlying the dysregulation of this pathway and identify potential therapeutic targets for cancer treatment.
Used in Personalized Medicine:
GDC-0339 is used in the context of personalized medicine to identify patients who are likely to benefit from MEK inhibitor therapy based on their genetic and molecular profiles. This approach aims to improve treatment outcomes and minimize side effects by tailoring therapy to individual patients' needs.

Upstream product

• 317336-73-5 (Z)-2,3,6,7-tetrahydroazepine-1-carboxylic acid tert-butyl ester 
• 18940-41-5 di(but-3-en-1-yl)amine 
• 1187056-39-8 N-(1-cyano-2-ethylperoxyethyl)-2,6-difluorobenzamide 
• 1270034-25-7 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid 
• 1263282-12-7 (Z)-2,3,6,7-tetrahydro-1H-azepine hydrochloride 

Relevant articles and documents

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

USP7 small-molecule inhibitors interfere with ubiquitin binding

The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival. However, developing selective deubiquitinase inhibitors has been challenging and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors. Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 ? distant from the catalytic cysteine. The compounds attenuate ubiquitin binding and thus inhibit USP7 deubiquitinase activity. GNE-6640 and GNE-6776 interact with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains. We investigated this idea by engineering di-ubiquitin chains containing differential proximal and distal isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquitin binding for full functional activity.