AGI-6780 / Agios Pharma - LARVOL DELTA

PREDICTING THE TRULY LOW-RISK PATIENTS WITH TNFRSF14 MUTATION USING MACHINE LEARNING ALGORITHMS IN DIFFUSE LARGE B CELL LYMPHOMA (EHA 2024) - " Clinical and mutation data from 2438 DLBCL patients receiving the R-CHOP like regimen in six public cohortswere analyzed...Based on the GDSC database, patients with high risk scoresexhibited higher sensitivity to some drugs than those with low risk and TNFRSF14wt patients, including histonedeacetylase (HDAC) inhibitor vorinostat (P=0...008), as well as the selective sulfonamide inhibitor of the IDH2/R140Q mutant AGI-6780 (P=0... TNFRSF14 is a favorable prognostic biomarker in DLBCL. Using machine learning algorithms, the truly low-riskTNFRSF14mut DLBCL patients were identified. Potential immunotherapeutic targets for future mechanism-based treatment in DLBCL was provided."

Clinical • IO biomarker • Machine learning • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • BTLA • CD8 • CTLA4 • IDH2 • TNFRSF14 • VTCN1

Significance of PBRM1 mutation in disease progress and drug selection in clear cell renal cell carcinoma. (PubMed, Biotechnol Genet Eng Rev) - "We also identified selective inhibitors for ccRCC with PBRM1 mutation using online databases such as PD173074 and AGI-6780...Although PBRM1 mutation did not show an association with ccRCC prognosis, a lower PBRM1 expression level correlated with worsened prognosis. Our study provides insights into the association of PBRM1 mutation with disease progression in ccRCC and suggests potential gene and signaling pathways for personalized treatment in ccRCC with PBRM1 mutation."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • PBRM1

DIA-based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia. (PubMed, Mol Cell Proteomics) - "To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for two months to generate derivative cells with mild, intermediate and severe resistance to the drugs as defined by their increasing resistance index (RI). In particular, IDH2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated IDH2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH2

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies (AACR 2018) - "...The Isocitrate Dehydrogenase 2 (IDH2) gene was identified as a top candidate, showing a synthetic lethal activity with the PI Carfilzomib (CFZ)...Consistently, combination of CFZ with either NAMPT (FK866) or SIRT3 (AGK7) inhibitors impaired IDH2 activity and increased MM cell death, thus phenocopying CFZ/AGI-6780 effects and putting the proteasome in a direct link with IDH2 inhibition. Finally, inducible IDH2 knock-down enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. In conclusion, our data demonstrate that IDH2 inhibition increases the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses, and broadening the application of PIs to other malignancies."

Leukemia • Mantle Cell Lymphoma • Multiple Myeloma

Generation and characterization of IDH1R132H and IDH2R140Q in vitro models for drug discovery and development (AACR 2018) - "In response to IDH2 specific inhibitors, AG-221 and AGI-6780, we demonstrated that IDH2R140Q TF-1 cells exhibited decreases in both cellular 2-HG and histone methylation levels. Taken together, these isogenic in vitro models are valuable tools for elucidating mechanisms involved in cancer-associated tumorigenesis and use in screening anti-cancer compounds for drug discovery and development."

Preclinical • Acute Myelogenous Leukemia

Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells. (PubMed, Cell Commun Signal) - "These results indicate that CP-17 can serve as a lead compound for the development of inhibitory drugs against AML with IDH2/R140Q mutant. Video abstract."

Journal • IDH1

Enasidenib Drives Maturation of Human Erythroid Precursors Independently of IDH2 (ASH 2019) - "First, we found that other IDH inhibitors (AG-120, AGI-6780, and AG-881) did not increase erythropoiesis at doses ranging from 1-10μM. Together, our data suggests that enasidenib drives maturation of CD71+ erythroid precursors independently of wildtype or mutant IDH2. Our results position enasidenib as a promising therapy to stimulate erythropoiesis and provide the basis for a clinical trial using enasidenib to improve anemia in a wide array of clinical contexts."

ABCG2 • CD123 • CD34 • CD36 • CD71 • FLT3 • GS • IDH1

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer. (PubMed, Theranostics) - "Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer."

Journal

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. (PubMed, Blood) - "...Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration-approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines...Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PIs to other malignancies."

Journal

Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q. (PubMed, Sci Rep) - "Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs. Our results suggest that conformational changes are the primary contributors to the inhibitory potency of the allosteric inhibitor. Our study will also facilitate the understanding of the inhibitory and selective mechanisms of AG-221 (a promising allosteric inhibitor that has been approved by FDA) for mutant IDH2."

Journal

IH2 INHIBITION ENHANCES PROTEASOME INHIBITOR RESPONSIVENESS IN HEMATOLOGICAL MALIGNANCIES (ICML 2019) - "...We have previously identified isocitrate dehydrogenase 2 (IDH2) as a synthetic lethal target that synergizes with the PI carfilzomib (CFZ)...Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PIs to other malignancies. Our preclinical studies, therefore, provide the rationale for the development of novel IDH2 inhibitors directed against wild-type IDH2."