Trethera at BioPharm America

September 7, 2017 – Trethera, a biotechnology company developing innovative small molecule inhibitors of cancer nucleotide metabolism, will be attending the BioPharma America conference in Boston, MA, September 26-27, 2017.

 

Trethera to attend RESI Boston 2017

September 7, 2017 – Trethera, a biotechnology company developing innovative small molecule inhibitors of cancer nucleotide metabolism, will be attending RESI Boston 2017 on September 26, 2017.

SOHO 2017 Annual Meeting

September 7, 2017 – Trethera will be attending the Society of Hematologic Oncology’s Annual Meeting, September 13-15, 2017, in Houston, Texas.

For more information on Trethera’s attendance, please contact info@trethera.com

ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways

Abstract

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.

Nat Commun. 2017 Aug 14;8(1):241. doi: 10.1038/s41467-017-00221-3.

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