MDM2 inhibitor for the treatment of cancers

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MDM2 inhibitor for the treatment of cancers

January 23, 2016 by larryhbern

MDM2 inhibitor for the treatment of cancers

Larry H. Bernstein, MD, FCAP, Curator

LPBI

AM 7209

ANTHONY MELVIN CRASTO, PhD

AM 7209

Amgen Inc. INNOVATOR

MF 747.700043 g/mol, C₃₇H₄₁Cl₂FN₂O₇S

cas 1623432-51-8

US8952036

p53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53 activation, tumor cells are under constant cellular stress from various insults including hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective advantage for inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of investigators have used mouse models to demonstrate that absence of p53 function is a continuous requirement for the maintenance of established tumors. When the investigators restored p53 function to tumors with inactivated p53, the tumors regressed.

p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and it is activated by gene amplification at incidence rates that are reported to be as high as 10%. MDM2, in turn, is inhibited by another tumor suppressor, p14ARF. It has been suggested that alterations downstream of p53 may be responsible for at least partially inactivating the p53 pathway in p53^WTtumors (p53 wildtype). In support of this concept, some p53^WTtumors appear to exhibit reduced apoptotic capacity, although their capacity to undergo cell cycle arrest remains intact. One cancer treatment strategy involves the use of small molecules that bind MDM2 and neutralize its interaction with p53. MDM2 inhibits p53 activity by three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53 degradation; 2) binding to and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction. In particular, this therapeutic strategy could be applied to tumors that are p53^WT, and studies with small molecule MDM2 inhibitors have yielded promising reductions in tumor growth both in vitro and in vivo. Further, in patients with p53-inactivated tumors, stabilization of wildtype p53 in normal tissues by MDM2 inhibition might allow selective protection of normal tissues from mitotic poisons.

The present invention relates to a compound capable of inhibiting the interaction between p53 and MDM2 and activating p53 downstream effector genes. As such, the compound of the present invention would be useful in the treatment of cancers, bacterial infections, viral infections, ulcers and inflammation. In particular, the compound of the present invention is useful to treat solid tumors such as: breast, colon, lung and prostate tumors; and liquid tumors such as lymphomas and leukemias. As used herein, MDM2 means a human MDM2 protein and p53 means a human p53 protein. It is noted that human MDM2 can also be referred to as HDM2 or hMDM2.

PATENT

US8952036

http://www.google.com/patents/US20140243372

Patent

WO 2015070224

Another particular MDM2 inhibitor is AM-7209 (Compound C herein), which is disclosed in U.S. provisional patent application number 61/770,901, filed February 28, 2013. (See Example No. 5 therein and below). AM-7209 has the following chemical name and structure: 4- (2-((3i?,5i?,65)-l-((5)-2-(tei’i-butylsulfonyl)-l-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)- 5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoic acid

Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction

Yosup Rew^*†, Daqing Sun†, Xuelei Yan†, Hilary P. Beck, et al.

J. Med. Chem., 2014, 57 (24), pp 10499–10511 http://dx.doi.org:/10.1021/jm501550p

http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2014/jmcmar.2014.57.issue-24/jm501550p/20141218/images/medium/jm-2014-01550p_0018.gif

Structure-based rational design and extensive structure–activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2–p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209(25), featuring improved potency (K_D from ITC competition was 38 pM, SJSA-1 EdU IC₅₀ = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED₅₀ = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED₅₀= 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1

Yosup Rew, Principal Scientist,

Amgen

March 2013 – December 2014 (1 year 10 months)San Francisco Bay Area

Medicinal Chemistry (oncology)
1. Led optimization of small molecule inhibitors targeting protein-protein interactions in oncology programs
2. Discovered AM-7209, a back-up clinical candidate of AMG 232 featuring improved potency (KD from ITC competition = 38 pM), by replacing the carboxylic acid with an 4-amidobenzoic acid