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.
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.
• 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
• 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
Prototype
This technology is available for licensing.
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.
Information available upon request.