Medchemexpress/LY2835219(Synonyms: ABEMACICLIB; CDK4/6 dual inhibitor)/HY-16297/5mg

LY2835219 a selective CDK4/6 inhibitor with IC₅₀ values of 2 nM and 10 nM for CDK4 and CDK6, respectively.

IC50: 2 nM (CDK4), 10 nM (CDK6)^[3]

LY2835219 reduces cell viability with the IC₅₀ values ranging from 0.5 μM to 0.7 μM, inhibits Akt and ERK signaling but not mTOR activation at head and neck squamous cell carcinoma (HNSCC) cells^[1]. LY2835219 shows inhibition on A375R1-4, M14R, and SH4R with EC₅₀ values ranging from 0.3 to 0.6 μM; LY2835219 inhibits the proliferation of the parental A375 and resistant A375RV1 and A375RV2 cells with similar potencies with IC₅₀ values of 395, 260, and 463 nM, respectively^[2]. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells^[3].

LY2835219 (45 mg/kg, p.o.) in combination with everolimus causes a cooperative antitumor effect in HNSCC xenograft tumor^[1]. LY2835219 (45 or 90 mg/kg, p.o.) shows significant tumor growth inhibition in an A375 xenograft model^[2].

• [1]. Ku BM, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget. 2016 Mar 22;7(12):14803-13.

  [2]. Yadav V, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol Cancer Ther. 2014 Oct;13(10):2253-63.

  [3]. Gelbert LM, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37.

  [4]. Wu T, et al. Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42.

Cells (5 × 10³) are plated in 96 well plates. Cells are treated the next day for 24 to 48 hours and then assessed for caspase-3 activity by Caspase-Glo-3/7 Assay, as per manufacturer"s instructions and a luminescence plate reader. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

LY2835219 is dissolved in DMSO to a 10 mM concentration. 

Cells are seeded in a 96-well plate, allowed to adhere overnight, and treated with DMSO control (0.1% v/v) or the indicated compounds for 72 h. Cell viability and proliferation are determined using a Cell Counting Kit according to the manufacturer"s instructions. The interaction between LY2835219 and mTOR inhibitor is determined using CompuSyn. Combination index (CI) values of 1 indicates and additive drug interaction, whereas a CI of < 1="" is="" synergistic="" and="" a="" ci="" of=""> 1 is antagonistic. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

LY2835219 is dissolved in 1% HEC in 20 mM phosphate buffer.

Six-week-old BALB/c female nude mice are injected subcutaneously with OSC-19 (1×10⁶) cells. When tumor sizes reach approximately 100 mm³, mice are randomized by tumor size and subjected to each treatment. At least 5 mice per treatment group are included. Each group of mice is dosed via daily oral gavage with vehicle, LY2835219 (45 mg/kg/d or 90 mg/kg/d), Everolimus (5 mg/kg/d), or a combination of both. The LY2835219 is dissolved in 1% HEC in 20 mM phosphate buffer (pH2.0). Tumor size and body weight are measured twice weekly. Tumor volumes are calculated using the following formula: V=(L × W²)/2 (L, Length; W, width). Mice are gavaged a final time on day 14 and sacrificed the following day. The tumors are removed for Western blot and immunohistochemistry. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Ku BM, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget. 2016 Mar 22;7(12):14803-13.

  [2]. Yadav V, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol Cancer Ther. 2014 Oct;13(10):2253-63.

  [3]. Gelbert LM, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37.

  [4]. Wu T, et al. Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42.

602.7

C₂₈H₃₆F₂N₈O₃S

1231930-82-7

Room temperature in continental US; may vary elsewhere

H₂O: ≥ 250 mg/mL

LY2835219 is dissolved in 1% HEC in 20 mM phosphate buffer (pH2.0) and administered orally by gavage (final volume 0.2 mL)^[4].

* "<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1]. Ku BM, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget. 2016 Mar 22;7(12):14803-13.

  [2]. Yadav V, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol Cancer Ther. 2014 Oct;13(10):2253-63.

  [3]. Gelbert LM, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37.

  [4]. Wu T, et al. Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42.