Abhisili is an oral inhibitor of cyclin dependent kinase CDK4/6. In HR+, HER2 breast cancer cells, CDK4 and CDK6 can promote the phosphorylation of retinoblastoma chemical book protein (Rb), and promote cell cycle progression and cell proliferation. Abemaciclib can inhibit the phosphorylation of Rb and block the progression of cells from G1 phase to S phase of the cell cycle, leading to cell aging and apoptosis.

On December 29, 2020, Eli Lilly announced its new anti-tumor drug, Only Select ® (Arbacilli Tablets) has been approved by the National Drug Administration (NMPA) for use in local advanced or metastatic breast cancer with hormone receptor positive (HR+) and human epidermal growth factor receptor negative (HER2-): (1) It is used as the initial endocrine therapy for postmenopausal women patients in combination with aromatic chemicalbook aromatase inhibitors. (2) Used in combination with Fluvistran for patients who have experienced disease progression after previous endocrine therapy. As a result, Abemaciclib became the second CDK4/6 inhibitor to be launched in China after Pembrolizumab.

The approval of Abemaciclib is based on the results of the critical phase III clinical study MONARCHplus. MONARCHplus is a randomized, double-blind, phase III clinical trial in Chinese women with HR+/HER2 postmenopausal advanced breast cancer. In the study, 306 patients received abexili or placebo combined with aromatase inhibitors (letrozole or anastrozole) as initial endocrine therapy (queue A), and 157 patients who progressed after endocrine therapy received abexili or placebo combined with fluvoxetine treatment (queue B). At the 2019 Annual Meeting of the European Society of Oncology (ESMO), the mid-term analysis results were announced, and the study reached its primary endpoint: in cohort A, compared with placebo, the median PFS of the combination group with abilelide was significantly prolonged, while the median PFS of the combination group with abilelide had not yet been reached. The nonsteroidal aromatase inhibitor (NSAI) monotherapy group reached 14.73 months (HR 0.499, P=0.001). In queue B, the median progression free survival (PFS) of the combination therapy group with Abexili was significantly prolonged compared to the monotherapy group with Fluvistran, at 11.47 vs 5.59 months (HR 0.376, P<0.001). As an oral CDK4/6 inhibitor, Abexili is the only approved monotherapy in this class for patients in the metastatic stage after endocrine therapy and previous chemotherapy. In addition, endocrine therapy combined with CDK4/6 inhibitors has become the standard treatment for HR+/HER2 mBC patients.

Abhisili combined with fulvestrant in the treatment of adult patients with advanced or metastatic breast cancer who are HR positive and HER2 negative. Verzenio is used alone to treat the same group of patients who have received endocrine therapy and chemotherapy but have experienced cancer metastasis.

Abemaciclib (LY2835219) is a selective cell cycle inhibitor for CDK4/6, with IC50 values of 2 nM and 10 nM in cell-free assays, respectively.

Production method ：Under nitrogen protection, a solution of 6- (2-chloro-5-fluoropyrimidin-4-yl) -4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole (5g, 15.5mmol), 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3.48g, 15.8mmol), potassium carbonate (4.71g, 34.1mmol), and xanthan acid (179mg, 0.3mmol) in tert amyl alcohol (25mL) was bubbled with nitrogen gas for 5 minutes. Subsequently, tris (dibenzylacetone) dipalladium (0) (142mg, 0.2mmol) was added, and the reaction mixture was heated to 100 ℃ and stirred for 19 hours until HPLC analysis showed complete conversion of pyrimidine benzimidazole. After the reaction is complete, the mixture is cooled to room temperature, diluted with dichloromethane, and filtered through a Whatman glass fiber filter. The filtrate was extracted with 4N hydrochloric acid aqueous solution (2 × 25mL), the aqueous phases were combined, activated carbon (250mg) was added and stirred, filtered (Whatman), and alkalized with 17% sodium hydroxide aqueous solution (30mL). The alkalized mixture was extracted with dichloromethane (2 × 20mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, it was stirred with Quadrasil (800mg), filtered again, and concentrated under reduced pressure. The remaining crude product is a yellow solid, which is slurried in acetone, filtered, washed with acetone, and dried under reduced pressure to obtain the target product in the form of a fine yellow powder. Yield: 4.5g (yield 57.3%), chemical purity: 99.4% (peak area at λ=320nm).

Boiling point	689.3 ± 65.0 ° C (Predicted)
Density	1.32 ± 0.1g/cm3 (Predicted)
Storage conditions	4 ° C, protectfrom light
solubility	Insoluble in water; DMSO ≥ 4.83 mg/mL, gently heated and sonicated; When heated gently, ethanol is ≥ 6.34 mg/mL
Acidity coefficient (pKa)	7.69 ± 0.10 (Predicted)
Form	Solid
Color	off white to yellow

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