Description:
This technology introduces highly potent and selective small-molecule inhibitors that block glutamine transport through the ASCT2 transporter, a critical metabolic gateway for many aggressive cancers. These compounds overcome the low affinity and poor specificity of existing inhibitors, enabling more effective therapeutic development and precise research applications targeting tumor metabolism.
Background:
Cancer cells rely heavily on glutamine uptake mediated by the ASCT2 transporter, but current ASCT2 inhibitors exhibit low potency, limited selectivity, and unsuitable drug-like properties. Most available compounds operate only at high micromolar concentrations and frequently inhibit related glutamate transporters, undermining their value as therapeutic candidates and research tools. These limitations impede efforts to disrupt tumor metabolism and to study amino acid transport mechanisms with precision, highlighting the need for more potent and selective inhibitors.
Technology Overview:
The invention provides novel competitive ASCT2 inhibitors that include cis-hydroxyproline derivatives and hydroxyhomoserine esters with inhibitory constants reaching sub-micromolar and even nanomolar levels. These compounds block glutamine transport by binding to ASCT2 with far higher affinity than prior inhibitors. A subset of hydroxyhomoserine esters also demonstrates strong selectivity for ASC transporters while avoiding inhibition of glutamate transporters, enabling precise targeting of glutamine uptake pathways.
Advantages:
• Achieves sub micromolar to nanomolar inhibitory potency
• Improves selectivity with respect to the glutamate transporters from the same family
• Enables more effective blockade of glutamine uptake in cancer cells
• Provides compounds suitable for in vivo therapeutic development
• Offers high value as selective research probes
• Addresses limitations of GPNA and other low-affinity inhibitors
Applications:
• Oncology drug development
• Neurological and visual disorder therapeutics
• Amino acid transport and metabolism research
• Cancer metabolism studies
• Pharmacological screening tools
Intellectual Property Summary:
• International PCT/US21/71989 PCT Filed 10/22/2021 WO 2022/087630 Nationalized
• United States 18/249,142 Utility Filed 04/14/2023 US2023-0416199 A1 Status: Filed
Stage of Development:
Prototype
Licensing Status:
This technology is available for licensing.
Licensing Potential:
Strong potential for pharmaceutical companies, biotechnology firms, and research institutions focused on oncology and metabolic diseases seeking high-affinity, selective inhibitors for therapeutic development and advanced biological studies.
Additional Information:
Information available upon request.
Inventors:
Christof Grewer, Elias Ndaru, Yueyue Shi, Laura Zielewicz
Alternate NCS Title: Next-Generation Potent and Selective ASCT2 Transport Inhibitors