1231930-82-7 Usage
Description
LY2835219, also known as Abemaciclib, is a potent and selective CDK4/6 inhibitor with potential antitumor effects. It is an orally-bioavailable compound that blocks phosphorylation of retinoblastoma protein, resulting in arrest of cell cycling in the G1 phase. Abemaciclib has demonstrated efficacy in various human tumor xenograft models and has been FDA approved for the treatment of advanced breast cancers.
Uses
Used in Oncology:
LY2835219 is used as an antitumor agent for the treatment of various solid tumors, including breast cancer, non-small cell lung cancer, glioblastoma, melanoma, colorectal cancer, and hormone receptor-positive breast cancer. It has shown efficacy in inducing a T cell inflamed tumor microenvironment and enhancing the efficacy of PD-L1 checkpoint blockade in breast cancer cells.
Used in Drug Development:
As a CDK4/6 protein kinase inhibitor, LY2835219 is used in the development of novel therapeutic agents for cancer treatment. Its dual inhibition of CDK4 and CDK6 makes it a promising candidate for combination therapies with other chemotherapeutic compounds to enhance antitumor action and overcome drug resistance.
Mechanism of action
Many human tumors acquire alterations, which can lead to the activation of cyclin-dependent kinases (CDKs)—CDK4 and CDK6. These alterations include mutations that directly activate CDK4 and CDK6, gene amplifications, which increase expression of various protein activators such as cyclin D, as well as genetic losses, which reduce expression of protein inhibitors such as p16.
Abemaciclib(previously known as LY2835219) specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
Current clinical trials
Abemaciclib(LY2835219) is being investigated in clinical trials in patients with breast cancer, non-small cell lung cancer, and pancreatic cancer, including a combination clinical trial in immuno-oncology.
As of early 2016 Abemaciclib is involved in 3 Phase III clinical trials:
The JUNIPER Study is comparing Abemaciclib against Erlotinib in patients with stage IV Non-small-cell lung carcinoma.
The MONARCH 2 study is investigating the effectiveness of Abemaciclib in combination with Fulvestrant for women with breast cancer. It is due to end in Feb 2017.
The MONARCH 3 study is investigating the effectiveness of Abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer. The trail is expected to end in June 2017.
Study in vivo
The dose percentage of LY2835219-MsOH treating brain was 0.5-3.9%. LY2835219-MsOH could treat subcutaneous and intracranial glioma models (U87MG), inhibiting tumor growth, and the effect is dose-dependent, whether alone or in combination with mozolomide.
References
http://www.lillyoncologypipeline.com/molecule/cdk-4-and-cdk-6-inhibitor/overview
https://en.wikipedia.org/wiki/Abemaciclib
https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=706364
References
1) Gelbert?et al.?(2014),?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,?32?825
2) Patnail?et al.?(2016),?Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-small Cell Lung Cancer, and Other Solid Tumors; Cancer Discov.,?6?740
3) Schaer?et al. (2018),?The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade; Cell Rep.,?22?2978
Enzyme inhibitor
This oral cell cycle inhibitor (FWfree-base = 506.61 g/mol; FWmesylate-salt = 602.70 g/mol; CAS 1231930-82-7 (mesylate salt)), also known as LY2835219 and N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5- fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2- pyrimidinamine, targets the cyclin-dependent kinase CDK4, or cyclin D1 (IC50 = 2 nM) and CDK6, or cyclin D3 (IC50 = 6 nM), inhibiting retinoblastoma (Rb) protein phosphorylation in early G1, thereby arresting the cell cycle in the G1, suppressing DNA synthesis, and inhibiting cancer cell growth. LY2835219 inhibits activation of AKT and ERK, but not mTOR.
Check Digit Verification of cas no
The CAS Registry Mumber 1231930-82-7 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,3,1,9,3 and 0 respectively; the second part has 2 digits, 8 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 1231930-82:
(9*1)+(8*2)+(7*3)+(6*1)+(5*9)+(4*3)+(3*0)+(2*8)+(1*2)=127
127 % 10 = 7
So 1231930-82-7 is a valid CAS Registry Number.
1231930-82-7Relevant articles and documents
CRYSTAL FORM OF ABEMACICLIB MESYLATE, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL COMPOSITION THEREOF
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Paragraph 0165-0170; 0171-0185, (2021/06/22)
Disclosed is a crystal form of abemaciclib mesylate, which has one or more improved properties compared with the known abemaciclib mesylate. Also involved are a method for preparing the crystal form of abemaciclib mesylate, a pharmaceutical composition and the use of same in the preparation of a drug for treating cancer diseases such as colorectal cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic granulocytic leukemia and acute granulocytic leukemia.
COMBINATION THERAPY FOR CANCER
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, (2015/09/28)
The present invention provides preparation of medicaments for use in treating and methods of treating non-small cell lung cancer in a patient comprising: [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H- benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, or a pharmaceutically acceptable salt thereof, in combination, as further described herein, with an anti-VEGFR2 antibody, preferably, ramucirumab.
