TAK-931 (SIMUROSERTIB)

Description

APIM050065: TAK-931 (SIMUROSERTIB), A Selective and ATP-Competitive Cell Division Cycle 7 (CDC7) Kinase Inhibitor

CAS No.: 1330782-76-7
IUPAC/Chemical Name: 2-(2S)-1-azabicyclo(2.2.2)oct-2-yl-6-(3-methyl-1H-pyrazol-4-yl)-thieno(3,2-d)pyrimidin-4(3H)-one
Molecular Formula: C₁₇H₁₉F₃N₅OS
Molecular Weight: 341.4
Purity: >99.7% chem and optical purity (by achiral and chiral HPLCs)
QC: Achiral and Chiral HPLCs, 1H-NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO (36.0mg/ml, 100mM)
Storage: Store at 0 °C (short term), -20 °C (long term), Desiccated
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

Cell division cycle 7 (CDC7) kinase is a serine/threonine kinase highly expressed in various types of cancer (eg, ovarian, breast, colorectal, and lung) and correlated with poor prognosis. It is involved in the DNA damage response as well as DNA replication, suggesting that CDC7 plays important roles in both cell proliferation during the S phase and genomic stability in the DNA damage response. CDC7 appears to be a critical gene for the proliferation and survival of cancer cells, and inhibition of CDC7 is expected to be antiproliferative and induce apoptosis in a broad range of cancers.[1]

TAK-931 (Cas No. 1330782-76-7) is a small molecule that inhibits CDC7 kinase and is currently under development for the treatment of patients with advanced malignancies. An open-label, dose-escalation, first-in-human study in adult patients with advanced nonhematologic tumors was conducted in Japan, and various dosing schedules were evaluated (NCT02699749). TAK-931 administered at 50 mg daily for 14 days in a 21-day treatment cycle was investigated in an open-label, phase 2 study in adult patients with metastatic pancreatic, colorectal, and other advanced solid tumors in the United States with a safety lead-in cohort to confirm comparable exposures and safety profiles between Asian and Western patients (NCT03261947). Clinical development was subsequently transitioned from a capsule to a tablet formulation. The relative bioavailability of tablets in reference to capsules was assessed.[1]

TAK-931 (Simurosertib) and its analogues were synthesized in eight steps from commercially available pentane-2,4-dione. [2]

Target: CDC7

IC₅₀: <0.3 nM

In Vitro: Simurosertib (TAK-931) potently inhibits CDC7 kinase activity (IC50 <0.3 nM) with a time-dependent ATP-competitive kinetics to its ATP-binding pocket. The selectivity studies using the 308 kinases reveals >120-fold selectivity of Simurosertib (TAK-931) for CDC7 kinase inhibition compared to other kinase inhibitions. Treatment with Simurosertib (TAK-931) suppresses the cellular MCM2 phosphorylation at Ser40 (pMCM2) in a dose-dependent manner, resulting in a delayed S phase progression, DNA-damage checkpoint activation, and caspase-3/7 activation. [3]

In Vivo: In the COLO205-xenograft mouse model, oral administration of Simurosertib (TAK-931) inhibits pMCM2 of the xenografted COLO205 in dose- and time-dependent manners. Furthermore, Simurosertib (TAK-931) exhibits a significant antitumor activity in multiple xenograft models. [3]

What is the solubility of TAK-931 (Simurosertib) in vitro?
75 mg/mL (219.66 mM; Need ultrasonic) (DMSO)

What is the solubility of TAK-931 (Simurosertib) in vivo?
1. Solvent: DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order; solubility ≥ 2.5mg/mL.
2. DMSO and 20% SBE-β-CD in salin
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order; solubility 2.5 mg/mL (need ultrasonic).
3. DMSO and corn oil
Please add 0% DMSO and 90% corn oil in order, solubility ≥ 2.5 mg/mL.

Reference:
[1]. Zhou, X. et al. et al. “Population Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Kinase Inhibitor, in Patients With Advanced Solid Tumors” J. Clin. Pharmacol. 2021, DOI: 10.1002/jcph.1974.
[2]. Kurasawa, O. et al. et al. “Discovery 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” J. Med. Chem. 2020, 63, 1084-1104.
[3]. Iwai, K. et al. “A Novel CDC7-Selective Inhibitor TAK-931 with Potent Antitumor Activity” Eur. J. Cancer 2016, 69, S34.
[4]. Shimizu, T. et al. “First-in-Human Phase 1 Study of TAK-931, an Oral Cell Division Cycle 7 (CDC7) Inhibitor, in Patients (pts) with Advanced Solid Tumors.” J. Clin. Oncol. 2018, 36, Meeting Abstract | 2018 ASCO Annual Meeting I.
[5]. Yu, J. et al. “Molecular Mechanism and Potential Target Indication of TAK-931, a Novel CDC7-Selective Inhibitor” Sci. Adv. 2019, 5, eaav3660.
[6]. Iwai, K. et al. “A CDC7-Selective Inhibitor, TAK-931, Suppresses Homologous Recombination Repair Activity to Enhance Antiproliferative Activity of a PARP Inhibitor” Eur. J. Cancer 2020, 138, S36.

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Additional information

Size	10 mg, 5 mg, 50 mg

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