^
    21d
    Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells. (PubMed, Nat Chem Biol)
    Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.
    Journal
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1)
    |
    IDH1 mutation • IDH wild-type • IDH1 R132
    |
    LY3410738
    4ms
    Final Results from a First-in-Human Phase 1 Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2 Mutations. (PubMed, Clin Cancer Res)
    LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus cisplatin-gemcitabine exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.
    P1 data • Journal • PD(L)-1 Biomarker • First-in-human
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation
    |
    cisplatin • Imfinzi (durvalumab) • gemcitabine • LY3410738
    5ms
    State of the Art of IDH Inhibitors: Emerging Questions and Perspectives. (PubMed, Anticancer Agents Med Chem)
    Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML...In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors...We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.
    Journal
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation
    |
    Tibsovo (ivosidenib) • Idhifa (enasidenib) • Voranigo (vorasidenib) • LY3410738
    7ms
    LOXO-IDH-20002: Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=200, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2025 --> May 2026
    Trial completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132
    |
    cisplatin • Imfinzi (durvalumab) • gemcitabine • LY3410738
    7ms
    LOXO-IDH-20001: Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=260, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2025 --> May 2026
    Trial completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132
    |
    Venclexta (venetoclax) • azacitidine • LY3410738
    over1year
    Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=200, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2024 --> May 2025
    Trial completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    cisplatin • Imfinzi (durvalumab) • gemcitabine • LY3410738
    over1year
    Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=260, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2024 --> May 2025
    Trial completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    Venclexta (venetoclax) • azacitidine • LY3410738
    2years
    A Study Comparing Different Formulations of LY3410738 in Healthy Adult Participants (clinicaltrials.gov)
    P1, N=60, Completed, Eli Lilly and Company
    New P1 trial
    |
    LY3410738
    2years
    A Study of LY3410738 in Healthy Adult Participants (clinicaltrials.gov)
    P1, N=42, Completed, Eli Lilly and Company
    New P1 trial
    |
    LY3410738
    over2years
    Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=260, Active, not recruiting, Eli Lilly and Company | Trial primary completion date: May 2024 --> Aug 2023
    Trial primary completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132 • IDH2 R140 • IDH2 R172
    |
    Venclexta (venetoclax) • azacitidine • LY3410738
    over2years
    Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=200, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2023 --> May 2024 | Trial primary completion date: May 2023 --> Aug 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132 • IDH2 R140 • IDH2 R172
    |
    cisplatin • Imfinzi (durvalumab) • gemcitabine • LY3410738
    almost3years
    Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P1, N=200, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132 • IDH2 R140 • IDH2 R172
    |
    cisplatin • Imfinzi (durvalumab) • gemcitabine • LY3410738