Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

Significance Statement

Low-hanging drug targets have been heavily exploited and potential for target breakthroughs is rare. To further the discovery of highly promising drug candidates, we have generated Pz-1, a next-generation targeted agent that is capable of equally shutting down two cancer survival pathways. Specifically, Pz-1 is capable of equally inhibiting VEGFR2 and RET at the same therapeutic dose. Therefore, tumor vasculature is arrested in combination with the inhibition of tumor growth. Synergistic efficacy is observed at extremely small, sub-milligram per kilogram oral doses in tumor xenografts. Pz-1 was discovered with a pioneering technique called ‘Synergistic Medicinal Chemistry’, or SMC, where an agent is strategically optimized to inhibit two or more cooperating disease targets. Unlike ‘drug-repurposing’, SMC enables the successful pursuit of ‘target-repurposing’. By targeting low-hanging drug targets that display cooperation in a variety of disease states, multiple inhibition profiles can be generated for unparalleled efficacy and to preemptively overcome drug resistance.

Figure Legend

The balance of inhibitory power has been achieved by creating an inhibitor that is equally-potent on both RET and VEGFR2. In their Communication in Angewandte Chemie International Edition, B. Frett et al. report the identification of a dual RET/VEGFR2 inhibitor that has been optimized for both targets to more successfully treat malignancies. This marks the next phase of targeted therapies where multiple drivers of disease can be effectively targeted with a single agent.

About the author

Brendan Frett, PhD — Dr. Brendan Frett has strong expertise in drug synthesis and therapeutic development. He is highly gifted at identifying new drug targets and producing next-generation agents that can modulate target activity. Previous work completed by Dr. Frett has led to the generation of two biotechnology companies and numerous authored and co-authored publications. Further, Dr. Frett has produced valuable intellectual property, where he is a co-inventor on three (3) patent applications, which are all associated with clinical candidate generation. He has collaborated with experts in the field of pharmacokinetics, pharmacology, intellectual property, and cancer biology. Dr. Frett is highly proactive at seeing projects through from concept to candidate. Along the drug discovery value chain, he has profound experience in drug synthesis, assay development, pharmaceutics, pharmacokinetics, and in vivo model development. His elemental talent in synthetic medicinal chemistry has set the foundation for unparalleled throughput in therapeutic development. He is co-founder and CEO/COO of Synactix Pharmaceuticals, Inc. and Promutech Pharmaceuticals, Inc.

About the author

Hong-yu Li, PhD — Dr. Hong-yu Li has extensive experience in drug discovery and development, with a particular focus on oncology. In 2001, Dr. Li was hired as a senior organic chemist at Eli Lilly & Co. and quickly climbed the ranks to research scientist and senior research scientist. Before leaving Lilly, he was a principle research scientist and team leader. He led medicinal chemistry teams with 20+ chemists and collaborated with leaders in pharmacology, pharmacokinetics, pharmacy, and intellectual property. Dr. Li and his team have successfully discovered three small molecule inhibitors that were tested in clinical trials; two of which are in Phase II clinical trials. Dr. Li was also the kinase platform-rational drug design leader at Lilly and was responsible for the generation of multiple kinase inhibitors. In this role, he also indirectly contributed to the generation of numerous additional clinical candidates. He has ten (10) patent/patent applications, which are all associated with clinical candidate generation. Dr. Li is also author and co-author on nearly 100 peer reviewed publications. He is a pioneer for the concept of synergistic medical chemistry. He co-founder and President of Synactix Pharmaceuticals, Inc. and Promutech Pharmaceuticals, Inc.

Journal Reference

Eur J Med Chem. 2015 Apr 13;94:123-31.

Frett B¹, McConnell N¹, Smith CC², Wang Y¹, Shah NP³, Li HY⁴.

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¹College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA.

²Division of Hematology/Oncology, University of California, San Francisco, CA, USA.

³Division of Hematology/Oncology, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.

⁴College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA; The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. Electronic address: [email protected].

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Abstract

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.

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