Robert Grotzfeld, Global Discovery Chemistry

Co-Mentor: Alexei Karpov, PhD

Global Discovery Chemistry

Basel, Switzerland

A priority research area for our New Modalities Group is to evaluate and further develop a variety of techniques for the targeted delivery of novel drug molecules to diseased tissue. The ultimate goal is to apply the most effective and innovative targeting strategies to the next generation of medicines, achieving excellent efficacy and vastly superior safety profiles compared to current treatments, thus bringing the maximum benefit to patients. We have developed expertise in targeted delivery of cytotoxic compounds into tumor tissues in the context of antibody-drug-conjugates (ADCs). Building on this experience, we will now look beyond ADCs and investigate the opportunities and limitations of passive targeted delivery approaches that rely on the enhanced permeability and retention effect. Drawing from our extensive experience in linker chemistry, we aim to design the next generation of tissue targeting systems that would release drugs only at the desired site of action, thus maximizing their therapeutic window.

One aspect of our approach is to evaluate dendrimers as carriers for drug delivery. Dendrimers represent a flexible and modular approach that will enable the exploration of specific drug release mechanisms in combination with tissue-targeting modalities. We aim to develop novel linkers and dendrimer scaffolds and evaluate biological activity of the resulting constructs in vivo.

Selected Publications

Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.
Jahnke W, Grotzfeld RM, Pellé X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL. 
J Am Chem Soc. 2010 May 26; 132 (20): 7043-7048. 

Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor.
Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, Bhagwat SS. 
J Med Chem. 2009 Dec 10; 52 (23): 7808-7816.

Click here for additional publications.