Ipatasertib-Akt Inhibitor

Creative Biolabs is a leader in antibody engineering, modification, and production. With years of accumulative work, we have established an advanced “DrugLnk” platform to provide highly customized strategies for antibody-drug conjugates (ADCs) and other targeted antibody therapeutics development using ipatasertib (GDC-0068) and derivatives as payloads.

Ipatasertib, also known as GDC-0068, is a strong ATP-competitive pan-AKT inhibitor. It was initially derived during the screening and optimization process of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds. Ipatasertib shows a powerful inhibition of all protein kinase B (Akt) isoforms but a weak suppression towards other members of the protein kinase family. Treatments of both tumor xenograft mouse models and human cancer cell lines with ipatasertib showed a significant suppression of Akt signaling, leading to a disruption in cell cycle progression and reduced cancer cell viability. Currently, the application of ipatasertib-paclitaxel combination in cancer therapies is under active evaluation in a variety of phase I and II clinical trials with promising results showing good dosage tolerance and drug efficacy against cancers such as metastatic triple‑negative breast cancer…

X-ray single-crystal structure of Ipatasertib mono-HCl (Org. Process Res. Dev., 2014).

Ipatasertib Mode of Action (MOA)

Akt, an abbreviated name for protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in the PI3K/Akt pathway as a regulator for a number of biological processes, including glucose metabolism, cell differentiation, and transcription. The mechanisms of the Akt pathway in tumorigenesis are complicated. On one hand, the activated Akt contributes to tumor anti-apoptotic activities through the inhibition of mitochondrial cytochrome c release or the regulation of other downstream effectors, including Bcl-2 family proteins, FOXO transcription factors and MDM2. On the other hand, Akt activation regulates cell cycle progression through the inhibition of glycogen synthase kinase 3beta, preventing the action of p21WAF1 and p27Kip1 via phosphorylation of AKT/mTOR kinases. As a highly selective and specific inhibitor of the activated Akt, ipatasertib not only exhibits dose-dependent inhibition of Akt signaling and potent antitumor activity, but also shows distinguished level of activities in cells with and without activated Akt signaling, making it an excellent choice as a new anti-cancer therapeutic agent.

The PI3K/Akt/mTOR signaling pathway (Left, Infect Agents Cancer, 2013) and X-ray structure of Ipatasertib bound to Akt1 (Right, J Med Chem, 2012), a process that inhibits Akt activity and down-regulates the subsequent signaling pathways in caner.

Ipatasertib-based ADCs

ADCs are composed of cytotoxic agents conjugated to monoclonal antibodies that target antigens differentially overexpressed on tumor cells. The strong cytotoxic agents are expected to induce cell death after being internalized into the tumor cell and released by various mechanisms. Studies have proven that ipatasertib was highly efficacious in a variety of tumor models and cancer cell lines. Based on its potent cytotoxicity, ipatasertib is considered to be a promising cytotoxic payload for the construction of ADCs. With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs are dedicated to help you develop Ipatasertib-linker complexes using readily available or customized linkers for antibody conjugation in a timely and cost-effective manner. Our customarily tailored services and high quality products will contribute greatly to the success of your projects.

Creative Biolabs also provides other various services regarding ADC development. Please feel free to contact us for more information and a detailed quote.

References：

1. Remarchuk, T.; et al. Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total synthesis and first kilogram scale-up. Org. Process Res. Dev. 2014, 18(12): 1652-1666.
2. Bhutani, J.; et al. Akt inhibitors: mechanism of action and implications for anticancer therapeutics. Infect Agents Cancer. 2013, 8(1): 49.
3. Blake, J.F.; et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012, 55(18): 8110-8127.