M-2698 (MSC2363318A)

Description

APIM050046: M-2698 (MSC2363318A) is an orally active, ATP competitive, selective p70S6K and Akt dual-inhibitor with IC₅₀s of 1 nM for p70S6K, Akt1 and Akt3. M-2698 can cross the blood-brain barrier and has anti-cancer activity.

CAS No.: 1379545-95-5
IUPAC/Chemical Name: (S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-8-carboxamide
Molecular Formula: C₂₁H₁₉ClF₃N₅O
Molecular Weight: 449.9
Purity: 99.8-100% by achiral and chiral HPLCs
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

The disorder of PI3K/Akt/mTOR (PAM) signaling pathway occurs in about 30% of human cancers, making it a reasonable target for new therapies. Specifically, the pathway is an important regulator of growth, proliferation, and metabolism. However, some PAM pathway inhibitors, such as Rapamycin complex (mTORC) rapalogs, cause the impairment of compensatory feedback circuits that lead to Akt activation. Besides, the incidence of PI3K Signal abnormalities in glioblastoma and breast cancer is particularly high. Therefore, the inhibition of the PAM pathway signal is a very attractive prospect for new anti-cancer therapy. Moreover, Rapamycin complex 1 (mTORC1) is a mammalian target of rapamycin against everolimus for the treatment of hormone receptor-positive. The signals sent by the PAM pathway lead to the activation of P70S6K, which directly affects the growth and survival of cells. M-2698 (MSC2363318A) (CAS No. 1379545-95-5) is an orally active, ATP competitive, selective p70S6K and Akt dual-inhibitor with anti-cancer activity.

But, how does M-2698 protect against cancer cells via p70S6K and Akt? Let’s discuss it in detail. In the beginning, M-2698 (MSC2363318A) is an orally active, ATP competitive, selective p70S6K and Akt dual-inhibitor with IC₅₀s of 1 nM for p70S6K, Akt1, and Akt3. In addition, M-2698 inhibits indirectly pGSK3β (IC₅₀=17 nM) and pS6 (IC₅₀=15 nM). Meanwhile, M-2698 inhibits proliferation in a dose-dependent manner in breast tumors cell lines with IC₅₀s of 0.02-8.5 µM. Nonetheless, M-2698 inhibits p70S6K activity and induces feedback loop phosphorylation on Akt and suppresses Akt activity in breast cancer cell lines. Importantly, M2698 can cross the blood-brain barrier. M2698 results in dose-dependent inhibition of tumor growth and tumor regression with the highest dose of 30 mg/kg. All in all, M2698 is an orally active, ATP competitive, selective p70S6K and Akt dual-inhibitor.

Target: p70S6K, Akt1, Akt3

IC₅₀: 1 nM

In Vitro: M-2698 (MSC2363318A) (0.3 nM to 50 M; 72 hours) inhibits proliferation in a dose-dependent manner in breast tumors cell lines with IC₅₀s of 0.02-8.5 µM. [1]
M-2698 (0.3, 1 µM; 24 hours) inhibits p70S6K activity and induces feedback loop phosphorylation on Akt and suppresses Akt activity in breast cancer cell lines. [1]
M-2698 inhibits indirectly pGSK3β (IC₅₀=17 nM) and pS6 (IC₅₀=15 nM). [1]

In Vivo: M-2698 (10-30 mg/kg/day; PO; 28 days) results in dose-dependent inhibition of tumor growth and results in tumor regression with the highest dose of 30 mg/kg. [1]
M-2698 (20 mg/kg/day; PO; 4 days) has a tumor:plasma exposure ratio of 12:1 over 24 hours and leads to increased levels of pAkt in tumor tissue. [1]
The mean total concentration of M-2698 after 16-hour infusion in rats is 1750 ng/g and 175 ng/mL in brain and plasma, respectively. [1]
M-2698 (po; 1, 5, 10, or 20 mg/kg/day; for 7 days) inhibits the phosphorylation of S6 in a dose-proportional manner over time after a single administration or daily treatments over 7 days. [1]

What is the solubility of M-2698 (CAS No. 1379545-95-5) in vitro?
DMSO: > 125 mg/mL

What is the solubility of M-2698 (CAS No. 1379545-95-5) in vivo?
1. DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order, solubility: ≥ 2.08 mg/mL.
2. DMSO and corn oil
Please add 10% DMSO and 90% corn oil in order, solubility: ≥ 2.08 mg/mL.

Reference:
[1]. Machl, A. et al. “M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier”, Am. J. Cancer Res., 2016, 6, 806-18.
[2]. Porter, W. et al. “Abstract 4710: Surface protein marker and single cell gene expression profiling of individual tumor cells dissociated from small cell lung cancer pdx mouse models can be correlated with in vivo sensitivity to the p70S6K/AKT1/3 inhibitor M2698”, Cancer Res., 2019, DOI: 10.1158/1538-7445.AM2019-4710
[3]. DeSelm, L. et al. “Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered Cancers”, J. Med. Chem., 2021, 64, 14603–14619.
[4]. Tsimberidou, A.-M. et al. “Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer”, J. Hematol. Oncol. 2021, 14, 127
[5]. Tsimberidou, A. M. et al. “Precision oncology: Results of a phase I study of M2698, a p70S6K/AKT targeted agent in patients with advanced cancer and tumor PI3K/AKT/mTOR (PAM) pathway abnormalities.”, J. Clin. Oncol., 2018, DOI: 10.1200/JCO.2018.36.15_suppl.2584.
[6]. Tsimberidou, A. M. et al. “P5.01 – A first in human, dose escalation trial of MSC2363318A – a dual p70S6K/Akt inhibitor, for patients with advanced malignancies”, Ann. Oncol., 2015, 26, ii25.

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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