• Code name : AGM-130
• Product name : Inditinib
• Therapeutic target : Oncology
• Indications : triple negative breast cancer (TNBC), Tamoxifen-resistant ER positive breast cancer
- AGM-130 is a highly selective, potent and reversible ATP-competitive inhibitor of cyclin dependent kinases (CDKs). CDKs have become emerging targets for the development of anti-cancer therapeutic drugs.
- CDKs affect cell growth and survival through several mechanisms, making the appropriate regulation of CDK activity important in various cellular processes. Inhibition of CDKs may provide an effective strategy for controlling tumor growth, making CDKs attractive targets for anticancer therapy.
- Molecular understanding has paved the way for the development of new agents that target pathogenic molecular alterations that drive tumor cell growth while sparing patients many of the traditional toxicities associated with chemotherapy. Ubiquitous to all cancer types is abnormal proliferation with dysregulation of normal cell cycle control. For this reason, inhibitors of key cell cycle regulators are attractive targets for novel cancer therapeutics. Selective CDK inhibition may provide therapeutic benefit against certain human neoplasia.
- Preclinical studies indicate that AGM-130 is a highly selective CDK inhibitor, which effectively inhibits CDKs signaling in tumors. Administration of AGM-130 in xenograft cancer animal models resulted in dramatic decrease of tumor progression with acceptable short-term and long-term animal toxicity profiles.
- Especially, AGM-130 is a cancer type specific anti-cancer agent, for triple negative, ER & PR+ breast cancers.
- Triple-negative breast cancer (TNBC) is a nasty form of the disease that does not respond to receptor-targeted therapeutics (Herceptin or Tamoxifen), as the receptors of interest (estrogen (ER), progesterone (PR), or HER-2) are not found in TNBC. The only marginally-effective treatments against TNBC are general chemotherapies, but overall response and survival rates are much lower in TNBC versus other breast cancers.
- AGM-130 development has been focused on an important group of solid tumors with unmet medical need, such as triple negative breast cancer, small lung cancer and melanoma, which will also benefit from this mechanism of action. These pathways affect disease progression and survival in solid tumors such breast cancer,
- AGM-130 is currently being evaluated in phase I clinical trial in patient with progressive or relapsing solid tumor in South Korea.
• The possible combination treatment of AGM-130 and other anti-cancer reagents - AGM-130 is intended for use as a single agent, or in combination with other anti-cancer agents, and will be used in patients with a variety of tumor types.
• Expansion of indication via adjustment of other cancers : non-small cell lung cancer etc.,
• Expansion of indication via the development of back-up drug candidates of AGM-130 (AGM-140, 145 and 147) : AGM-130 development can be used in the treatment of hematologic malignancies, including acute and chronic lymphocytic leukemia (CLL), based on the consistent anti-tumor activity that has been observed across a broad spectrum of cancer models, including those resistant to currently available therapies.
• Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that the uptake of premium-priced agents will fuel 5 percent annual growth in the breast cancer market, with sales reaching more than $15 billion in 2022 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan
• AGM-130 is a highly selective, potent and reversible ATP-competitive inhibitor of cyclin dependent kinases (CDKs). CDKs have become emerging targets for the development of anti-cancer therapeutic drugs.
• The validation of anti-proliferative activity of AGM-130 in breast cancer cell lines comparing with Pfizer's Palbociclib
• Palbociclib will eventually improve the cure rate for all patients with ER-positive, HER2-negative breast cancer, including those with early-stage disease whereas AGM-130 works against Triple-negative cancers.
• No adverse effect were observed based on general appearance, weight loss or reduction in weight gain after treatment of AGM-130 can be given in patients with metastatic triple negative breast cancer and tamoxifen-resistant ER-positive breast cancer
Technical Highlighted Summary
Method of Admin. Test System Results
In vitro In vitro kinase reactions In vitro kinase activities of CDK1, 2, 4, 5 and 6 was inhibited with an IC50 of 1.9 ~ 59.8 nM (AGM-130) and 0.2 ~ 0.5 nM (Roscovitine), 3.1 ~ 65.4 nM (Staurosporin)
In vitro kinase reactions
(40 different kinases) In vitro kinase activity of Flt4(h), ckit(V560G)(h), CDK2,5,6, HIPK2(h), Fms(h) and ARK5(h) was inhibited by AGM-130 by more than 90 % at 100 nM
NIH 60 cell lines screening -In breast cancer cell lines, AGM-130 showed a good growth inhibition. In melanoma and lung cancer cell lines, AGM-130 showed lethality.
18 Breast cancer cell lines screening 4 types of Her2 positive breast cancer cell lines showed relatively insensitive with IC50 values higher than 3 μM, whereas the growth of 3 types of ER positive and 7 of 10 types of triple negative cell lines was potently inhibited with IC50 values below 1 μM.
In vivo The effect of AGM-130 on cell proliferation in HUVECs and mES cells cell cytotoxicity was not observed (IC50 > 10,000 nM)
anti-tumor effect of AGM-130 in various xenograft models The anti-tumor activity of AGM-130 was not observed in KB (oral cancer cell line) and HCT116 (colon cancer cell line) xenograft experiments, but in A549 (lung cancer cell line) and MDA-MB-231 (triple negative breast cancer cell line) xenograft experiments.
AGM-130 also significantly inhibited tumor progression in the xenograft animal model with MCF-7 cells in a dose-dependent manner. Consequently, AGM-130 is a cancer type specific anti-cancer agent, especially for triple negative, ER & PR+ breast cancers.
Anti-cancer drugs, triple negative breast cancer (TNBC), tamoxifen-resistance, CDK inhibitors, indirubin derivatives, clinical trial