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Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities

Significance Statement

Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities. global medical discovery

 

 

 

 

 

Carmolex’s re-engineering of early stage drug discovery shift’s the balance in favor of its bio-pharma clients and visionary investors

To date, most drug discovery efforts fail because researchers are only able to sample a tiny portion of chemical space (protein targets), with libraries that are less than one million molecules in size. Carmolex’s “Google” like platform, proprietary virtual small molecule libraries, (billions) and world-class mastery of Multi Component Chemistry (MCR) empower it to be the most innovative engine for drug precursor discovery available.

Carmolex’s commercial ability to take full advantage of the enormous variety of protein-protein interactions (PPIs) underlying the thousands of disease processes still afflicting humanity have been described by some experts as a ”golden” therapeutic and business opportunity.

Carmolex’s much more rational and targeted approach with innovative software capabilities (AnchorQueryTM), constantly expanding libraries of proprietary molecules (currently over 390 million/6 billion 3-D variations) and a special collection of master key reactions (InstantChemTM) increase the likelihood of successfully designing, screening and delivering superior “starting points” by several orders of magnitude.

With bio-pharma’s anxious about expiring patents and urgency to refill their drug pipelines Carmolex’s fee for service revenue model and near term prospects for sustainability are good. Funds are being raised for:

  • Continued build out of the largest, most representative virtual small molecule library in the world
  • Administrative overhead, recruitment of additional Scientific, Sales and Business Development Staff
  • Carmolex is also advancing ”hot” targets of academic/commercial interest as an internal pipeline of “Early Molecular Entities,” in order to possibly generate even more valuable IP sales and the formation of important drug development partnerships

Interestingly, review of some pre-revenue, conventional, totally pipeline dependent bio-techs listed on NASDQ reveals that they are able to command valuations in excess of $100 million. By comparison Carmolex presents a compelling entry point opportunity because it’s multiple revenue streams and widely applicable know-how/IP reduce risk, increase the probability of near term viability and provide a foundation to achieve recurrent mid and long term profitability and stock appreciation.

 

Rafael Vélez, MD
CEO Carmolex, Inc.
4415 Fifth Avenue, Suite #106
Pittsburgh, Pennsylvania 15213
[email protected]
+1 412-223-9772 ext.11
www.carmolex.com

 

acute myeloid leukemia

 

 

 

 

 

 

Huang Y, Wolf S, Beck B, Köhler LM, Khoury K, Popowicz GM, Goda SK, Subklewe M, Twarda A, Holak TA, Dömling A.

ACS Chem Biol. 2014 Mar 21;9(3):802-11.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, United States.

Abstract

The inhibition of p53-MDM2 interaction is a promising new approach to non-genotoxic cancer treatment. A potential application for drugs blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE.

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