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Updated: Jan 13, 2026
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
A Novel Allosteric Inhibitor Targeting IMPDH at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma
Nagarajan Pattabiraman1, Cosimo Lobello2, David Rushmore2
1Veracure Biosciences Inc., Silver Spring, MD 20901, USA.
Background/Objective:
Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target.
Methods:
Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines.
Results:
Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA.
Conclusion:
These findings uncover a novel TK-IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers.
Insights
Oncogenic tyrosine kinases (TKs) regulate inosine monophosphate dehydrogenase 2 (IMPDH2) activity through phosphorylation. A novel inhibitor, Comp-10, targets IMPDH2 allosterically, offering a promising therapeutic strategy for TK-driven cancers.
Area of Science:
- Biochemistry
- Molecular Oncology
- Drug Discovery
Background:
- Oncogenic tyrosine kinases (TKs) like ALK and SRC are crucial in cancer progression.
- The impact of TK signaling on metabolic enzymes, specifically IMPDH2, remains largely uncharacterized.
- IMPDH2 is a key enzyme in purine biosynthesis, essential for cancer cell proliferation.
Purpose of the Study:
- To investigate the regulation of IMPDH2 by TK signaling.
- To explore IMPDH2 as a potential therapeutic target in cancer.
- To identify and develop novel inhibitors of IMPDH2.
Main Methods:
- Phosphoproteomic screening and in vitro kinase assays identified IMPDH2 phosphorylation sites.
- Lipid-binding assays assessed the role of PI3P in IMPDH2 regulation.
- Structure-based virtual screening yielded allosteric IMPDH inhibitors tested in lymphoma models.
Main Results:
- IMPDH2 was identified as a novel substrate for ALK and SRC, with phosphorylation at Y233 enhancing its activity.
- Phosphatidylinositol 3-phosphate (PI3P) was found to be a natural lipid inhibitor of IMPDH2.
- A novel allosteric inhibitor, Comp-10, was developed, which reduced IMPDH1/2 protein levels and inhibited growth in resistant lymphoma cells, unlike MPA.
Conclusions:
- A new TK-IMPDH2 signaling pathway was discovered, revealing allosteric regulation mechanisms.
- Comp-10 demonstrates efficacy against TK-driven cancers by targeting metabolic vulnerabilities.
- Comp-10 offers a promising therapeutic candidate for tyrosine kinase-driven malignancies.
