-Fluoro-2-methylimidazo[1,2-a]pyridin-6-amine cas 1643412-36-5

· CAS Number: 1643412-36-5
· Chemical Name: (9S)-9-[4-(5-chloro-4-{[2-(dimethylamino)ethyl]amino}pyridine-2-yl)amino phenyl]-8,10,11,13-tetrahydro-9-methyl-7H-pyran[4",3":4',5"]pyrrolo[4',3':4,5']pyrrolizol-7-one
· Development Stage: Preclinical research (as of the end of 2023)
· Target: B-cell lymphoma factor-2 (BCL-2)
· Main Indications: Hematological malignancies (such as acute myeloid leukemia AML, lymphoma, etc.) and solid tumors.
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Detailed Introduction
What is it?
From a chemical structure perspective, it is a derivative or optimized compound of Venetoclax. Venetoclax (Venclexta, a commercial name) is the world's first and highly successful BCL-2 inhibitor, jointly developed by AbbVie and Roche. TQB3905 aims to achieve better efficacy, lower drug resistance, or superior pharmacokinetic properties than Venetoclax through structural optimization.
2. Mechanism of Action
Its mechanism of action is highly similar to that of Venetoclax. The core principle is to exert anti-tumor effects by inducing apoptosis in cancer cells.
· Background: BCL-2 is an anti-apoptotic protein that is overexpressed in many cancer cells. It acts like a "brake", preventing cells from initiating the normal programmed death (apoptosis) process, thereby causing cancer cells to proliferate and survive indefinitely.
· Function: TQB3905 can highly selectively bind to the BCL-2 protein and inhibit its function. This is equivalent to "unlocking" the death brake of cancer cells.
· Result: Once BCL-2 is inhibited, the permeability of the outer mitochondrial membrane increases, releasing cytochrome C and other pro-apoptotic factors, ultimately activating the caspase proteinase cascade reaction, leading to the irreversible apoptosis of cancer cells.
3. Development Background and Objectives
Although Venetoclax has achieved significant success in clinical applications, it still faces some challenges:
· Drug resistance: Some patients may develop resistance to Venetoclax.
· Side effects: The main side effect is tumor lysis syndrome, and a cautious dose escalation is required.
· Indications limitation: It is mainly applicable to hematological tumors, and has limited efficacy for solid tumors.
4. Preclinical research data
According to publicly available patents and abstracts from academic conferences, TQB39405 demonstrated excellent characteristics in preclinical studies:
· High efficacy: In in vitro cell experiments, it demonstrated extremely strong abilities to inhibit proliferation and induce apoptosis in various hematological tumor cell lines (such as RS4;11, an acute lymphoblastic leukemia cell line), with its efficacy (IC50 value) reaching the picomolar level, which is very potent.
· High selectivity: The selectivity for BCL-2 is much higher than for other proteins in the same family (such as BCL-xL, MCL-1). This high selectivity is very important because inhibiting BCL-xL can cause severe side effects such as thrombocytopenia.
· In vivo efficacy: In mouse models with human tumors (CDX), TQB3905 can significantly inhibit tumor growth and even lead to complete tumor regression, and its effect is superior to or comparable to Venetoclax.
· Overcoming resistance: In some cell models resistant to Venetoclax, TQB3905 still shows activity, indicating that it may be effective for some patients with resistance.
5. Application Prospects
· Monotherapy: Similar to Venetoclax, TQB3905 may initially be developed for the treatment of blood cancers that rely on BCL-2, such as acute myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma, etc.
· Combination therapy: The greater potential lies in its use in combination with other anti-cancer drugs. For example:
· Combined with demethylating drugs (azacitidine, decitabine) for the treatment of AML.
· Combined with CD20 monoclonal antibody (such as rituximab) for the treatment of CLL.
· Combined with other targeted drugs or chemotherapy drugs to overcome drug resistance.