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Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

Abstract

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

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Fig. 1: Flow diagram summarizing the AML and Solid Tumor trials and clinical analyses.
Fig. 2: Drug-related toxicity.
Fig. 3: Evidence of target inhibition in AML blasts.
Fig. 4: IACS-010759 induces physiological and behavioral symptoms of peripheral neuropathy in preclinical models.

Data availability

Requests for access to patient-level data from these trials should be made to the corresponding authors. For each request, an independent review panel at MD Anderson Cancer Center will convene within 30 days of the request and decide whether the data will be provided; the data will then be available for up to 12 months. Source data are available for Figs. 2, 3a–d, 3f–k, 4, and Extended Data Figs. 18, 9a, 9c-f, 9h, 10. Source data are provided with this paper.

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Acknowledgements

We thank S. Hammonds Nelson for providing help with clinical data verification. This research is in part supported by the MD Anderson Cancer Center Leukemia (NIH no. SPORE P50 CA100632 (M.K.), NIH no. R01 CA206210 (M.K. and S.T.), NIH no. R01 CA227064 (A.K. and C.J.H.), CPRIT no. RP180309 (M.K.), NIH Clinical Translational Science Award no. 1UL1TR003167 (D.D.K.), MD Anderson Cancer Center support grant no. P30 CA016672, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Grant and the Leukemia & Lymphoma Society through its Therapy Acceleration Program and by the MD Anderson Moon Shots program. The CPRIT Core is supported by CPRIT Core Facility Support Grants (nos. RP120348 and RP170002).

Author information

Authors and Affiliations

Authors

Contributions

Clinical studies were designed and initiated by T.A.Y., N.D., F.M.-B., C.K.-M., C.P.V., T.P.H., P.J., J. R. Marszalek and M.K. Collection and analysis of clinical data were conducted by T.A.Y., N.D., F.M.-B., C.K.-M., C.P.V., T.P.H., P.J., J. R. Marszalek, M.K., C.S., M.B.B., E.E.D., S.F., D.S.H., D.D.K., S.A.P.-P., J.R., V.S., S.P. and A.M.T. Several patients were recruited by N.P., F.R., M.Y., E.J.J., M.O., K.S., P.B., N.B. and H.M.K. PK analyses and related figures were generated by S. Gera, J. R. Marszalek and Q.A.X. PD analyses in AML blasts and related figures were generated by S.T., M.M., M.E.C., Q.Z., J.H. and A.L. Transcriptomic analyses, data analyses and related figures and tables were generated by C.P.V., C.A.B., Y.L. and Z.J. Preclinical studies and related figures were generated by C.J.H., A.K., J.Z., J.P.G., M.E., D.F. and J. R. Molina. The manuscript was written by T.A.Y., N.D., F.M.B., C.P.V., T.H., P.J., J. R. Marszalek, M.K. and S. Gao. All authors reviewed the manuscript before submission.

Corresponding authors

Correspondence to Timothy A. Yap, Philip Jones, Joseph R. Marszalek or Marina Konopleva.

Ethics declarations

Competing interests

T.A.Y. is the Medical Director of the Institute for Applied Cancer Science (M.D Anderson Cancer Center), which has a commercial interest in DDR and other inhibitors (no. IACS30380/ART0380 was licensed to Artios). T.A.Y.’s research has been supported by Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith; he has consulted for AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol-Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio; he is a stockholder in Seagen. N.D. has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium and ImmunoGen and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs and Agios. M.K. has received research funding from AbbVie, Genentech, F. Hoffman La Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, AstraZeneca, Rafael Pharmaceutical, Sanofi and Forty-Seven and has served in a consulting or advisory role for AbbVie, Genentech, F. Hoffman La Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji and Janssen. N.P. serves on the Board of Directors for the following: Dan’s House of Hope; Consulting: AbbVie, Aptitude Health, Astellas Pharma US, Inc., Blueprint Medicines, Bristol-Myers Squibb, Celgene Corp, Cimeio Therapeutics AG, ClearView Healthcare Partners, CTI BioPharma, Dava Oncology, Immunogen, Incyte, Intellisphere, LLC., Novartis AG, Novartis Pharmaceuticals Corp, OncLive (Owned by Intellisphere, LLC), Patient Power, PharmaEssentia, Protagonist Therapeutics, Sanofi-aventis, Stemline Therapeutics, Inc. and Total CME; financial relationships (for example, Stock, Royalty, Gift, Employment or Business Ownership): Karger Publishers; Scientific/Advisory Committee Member: Cancer.Net, CareDx, CTI BioPharma, EUSA Pharma, Inc., Novartis Pharmaceuticals Corp, Pacylex, PharmaEssentia; Speaker/Preceptorship: AbbVie, Aplastic Anemia & MDS International Foundation, Curio Science LLC, Dava Oncology, Imedex, Magdalen Medical Publishing, Medscape, Neopharm, PeerView Institute for Medical Education, Physician Education Resource (PER), Physicians Education Resource (PER), Postgraduate Institute for Medicine, Stemline Therapeutics, Inc. F.M.-B. consults for AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor and Zymeworks; serves on the advisory committee for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals and Zentalis; and has received honoraria from Chugai Biopharmaceuticals; leads clinical trials that are funded or sponsored by Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc. and Taiho Pharmaceutical Co. P.B. recieves research funding from Incyte, BMS, CTI BioPharma, Constellation (now Morphosys), Kartos, Blueprint Medicines, Cogent Biosciences, Ionis, Pfizer, Astellas, NS Pharma and Promedior, and honoraria from Incyte, BMS, CTI BioPharma, Sierra Oncology (now GSK), Blueprint Medicines, Cogent Biosciences, Abbvie, Karyopharm, Pharma Essentia, Novartis, Constellation (now Morphosys) and Kartos. A.M.T. is funded by OBI Pharma, Agenus, Parker Institute for Cancer Immunotherapy, Tvardi Therapeutics, Tempus, IMMATICS; Consulting or Advisory Roles: Vincerx, Diaccurate, BrYet, NEX-I, Macrogenics and BioEclipse. J.R. serves on the advisory board of Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners and IONCTURA; receives research funding from Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d’Hebron Institute of Oncology/Cancer Core Europe; receives clinical research support from Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics and Mirati Linnaeus Therapeutics; and receives travel support from the European Society for Medical Oncology. IACS-010759 was developed by scientists at MD Anderson. If this drug becomes FDA approved and commercially available, MD Anderson will profit from its sale. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Chi Dang, Daniel Pollyea, Juliane Gust and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Saheli Sadanand and Joao Monteiro, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Effect of IACS-010759 on venous lactate and blood pH.

ad, Relationship between venous lactate and IACS-010759 concentrations in AML (a) cohort 1, (b) cohort 2, (c) cohort 3, and (d) cohort 4. Dotted line indicates 8 nM of plasma IACS-010759. e-h, Relationship between blood pH and plasma IACS-010759 concentrations in AML (e) cohort 1, (f) cohort 2, (g) cohort 3, and (h) cohort 4. Dotted line indicates 8 nM of plasma IACS-010759. i-m, Relationship between venous lactate and IACS-010759 concentrations in Solid Tumor (i) cohort 1, (j) cohort 2, (k) cohort 3, (l) cohort 4, and (m) cohort 5. Dotted line indicates 8 nM of plasma IACS-010759. n-r, Relationship between blood pH and plasma IACS-010759 concentrations in Solid Tumor (n) cohort 1, (o) cohort 2, (p) cohort 3, (q) cohort 4, and (r) cohort 5. Dotted line indicates 8 nM of plasma IACS-010759.

Source data

Extended Data Fig. 2 Treatment-induced peripheral neuropathy.

a, b, (a) Ultrastructural examination and (b) electronic microscopy analysis of a biopsy collected from the left superficial peroneal upper leg nerve root of a Cohort 4 patient from the Solid Tumor trial. The patient developed Grade 3-4 peripheral neuropathy while on a treatment regimen of 2.5 mg of IACS-010759 daily during the induction phase (Day 1–7), and 2.5 mg bi-weekly during the maintenance phase. Images indicate severe vacuolar changes in myelin sheath with axonal degenerative changes and atrophy.

Extended Data Fig. 3 Pharmacokinetics of IACS-010759 in AML and Solid Tumor cohorts.

Dosing regimens are detailed in Fig. 1, Supplementary Table 1. a, b, Plasma IACS-010759 concentrations over time in (a) AML Cohort 1 (blue) and Cohort 2 (red); (b) AML Cohort 3 (green) and 4 (purple). c, d, Plasma IACS-010759 concentrations (nM) over time in Solid Tumor (c) Cohort 1 (blue), Cohort 2 (red), and Cohort 3 (green); (d) Cohort 4 (purple), Cohort 5 (orange), and Cohort 6 (black). Each dot represents the mean plasma IACS-010759 concentration at one collection point for one patient.

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Extended Data Fig. 4 Plasma IACS-010759 concentrations in individual patients.

Dosing regimens are detailed in Fig. 1, Supplementary Table 1. a, b, Plasma IACS-010759 concentrations AML patients in (a) Cohort 1 (red) and Cohort 2 (blue), which each received QD dosing, as well as in (b) Cohort 3 (red) and Cohort 4 (blue), which each received an induction and maintenance phase. c-e, Plasma IACS-010759 concentrations in Solid Tumor (c) Cohorts 1 (blue) and 5 (orange), (d) Cohorts 2 (purple) and 4 (red), (e) Cohort 3, and (f) Cohort 6. All cohorts received induction and maintenance phases.

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Extended Data Fig. 5 Correlations between plasma IACS-010759 concentration and baseline oxygen consumption rate (OCR) from AML blasts.

Baseline OCR has been normalized to cell number. Closed circles are predose and open circles indicate post dose values. Blue indicates pre-dose (C1D1). Red indicates after one week of QD dosing (C1D7 - Cohorts 3, 4; C1D14 - Cohorts 1, 2). Black closed circles are other timepoints collected during cycle 1. Correlations analyzed by a two-tailed Pearson’s correlation coefficient test; p < 0.05. Each symbol represents the mean +/− 95% confidence interval derived from technical replicates. a, n = 3 at C1D8(6), C1D10; n = 5 at C1D1, C1D1(6) C1D8, and C1D14; n = 6 at all other times. b, n = 5 at C1D8, C1D8(6), C1D22(6), C1D28, C1D28(6); n = 6 at all other times. c, n = 6. d, n = 2 at C1D9, C1D14(6), C1D25(6), C1D28, C1D28(6); n = 3 at C1D8, C1D8(6), C1D14, C1D17, C1D17(6); n = 4 at C1D2, C1D10; n = 5 at C1D1, C1D1(6). e, n = 5 at C1D10; n = 6 at all other times. f, n = 4 at C1D8(6); n = 6 at all other times. g, n = 4 at C1D1(4); n = 5 at C1D1; n = 6 at all other times. h, n = 6. i, n = 2 at C1D7(4); n = 3 at C1D7, C1D15, C1D15(4), n = 6 at C1D1, C1D1(4). jk, n = 6. l, n = 3 at C1D1, C1D1(4); n = 4 C1D7, C1D7(4); n = 6 at all other times.

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Extended Data Fig. 6 Correlations between plasma IACS-010759 concentration and maximal oxygen consumption rate (OCR) from AML blasts.

Maximal OCR has been normalized to cell number. Closed circles are predose and open circles are post dose values. Blue indicates pre-dose (C1D1). Red indicates after one week of QD dosing (C1D7 - Cohorts 3, 4; C1D14 - Cohorts 1, 2). Black closed circles are other timepoints collected during cycle 1. Correlations analyzed by a two-tailed Pearson’s correlation coefficient test; p < 0.05. Each symbol represents the mean +/− 95% confidence interval derived from technical replicates. a, n = 3 at C1D8(6), C1D10; n = 4 at C1D1, C1D2, C1D8; n = 5 at C1D1(6), C1D14, C1D14(6), n = 6 at all other times. b, n = 4 at C1D28, C1D28(6); n = 5 at C1D8, C1D8(6), C1C14, C1C14(6), C1D22(6); n = 6 at all other times. c, n = 6. d, n = 1 at C1D17; n = 2 at C1D9, C1D14, C1D14(6), C1D25(6), C1D28, C1D28(6); n = 3 at C1D8, C1D8(6), C1D17(6); n = 4 at C1D2, C1D10; n = 5 at C1D1, C1D1(6). e, n = 4 at C1D10; n = 6 at all other times. f, n = 4 at C1D8(6); n = 5 at all other times. g, n = 4 at C1D1(4), C1D15; n = 5 at C1D1, C1D15(4), C1D21, n = 6 at C1D7, C1D7(4). H, n = 5 at C1D15, C1D15(4); n = 6 at all other times. i, n = 2 at C1D7(4), C1D15; n = 3 at C1D7, C1D15(4); n = 6 at C1D1, C1D1(4). j, n = 5 at C1D1, C1D1(4), C1D21, unscheduled collection time point; n = 6 at all other times. k, n = 3 at C1D15, C1D15(4); n = 6 at all other times. l, n = 2 at C1D1; n = 3 at C1D1(4); n = 4 at C1D7, C1D7(4); n = 5 at C1D21; n = 6 at C1D15, C1D15(4), end of study.

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Extended Data Fig. 7 Evidence of target inhibition in AML blasts.

a-e, Effect of IACS-010759 on levels of (a) NAD+, (b) nicotinamide, (c) tryptophan, (d) glutamine, or (e) alanine in AML blasts from Patients 16, 17, and 19 from AML Cohort 4. Y-axis shows metabolite levels relative to pre-dose levels. N = 4, n = 7, or n = 5 biologically independent samples for Patients 16, 17, or 19 respectively. Differences from pre-trial levels analyzed by a simple linear regression. g-f, Effect of IACS-010759 exposure on NMP, NDP, and NTP levels in AML blasts from (f) Patient 19 and (g) Patient 16 from AML Cohort 4. Y-axis shows nucleotide levels respective to pre-dose levels. N = 4 biologically independent samples. Differences from pre-trial levels analyzed by a simple linear regression.

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Extended Data Fig. 8 Drug-induced effects on gene expression in AML blasts.

a, Gene Ontology enrichment analysis on RNA-sequencing (RNA-seq) results from AML blasts collected from Patients 16, 17, and 19 of AML Cohort 4 at several pre- and post-dose timepoints across Cycle 1. b, Pathway analysis ranking deregulated biological pathways upon IACS-010759 treatment from patients described in (a).

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Extended Data Fig. 9 IACS-010759 elevates plasma lactate as well as induces behavioral and physiological changes indicative of peripheral neuropathy in preclinical models.

a, Effect of escalating doses of IACS-010759 or vehicle on plasma lactate in NSG and B6 mice. n = 4 or n = 5 biologically independent samples from vehicle-treated mice or all other groups, respectively. Data analyzed by two-tailed unpaired Student’s T-test; n.s. = non-significant. Mean ± SE shown. b, Schematic of the Conditioned Place Preference (CPP) Test. c, Spontaneous pain assessed with a CPP test (b) after the last dose of IACS-010759 (n = 6) or vehicle (n = 6). Data analyzed by two-sided unpaired Student’s T-test. Mean ± SE shown. d, Sensorimotor function of mice in (c) assessed with a beam walk test. n = 12 biologically independent samples. Data analyzed with a two-way ANOVA with Tukey’s multiple comparison test. Mean ± SE shown. e, Oxygen consumption rate (OCR) in the dorsal root ganglion (DRG) from mice in (c) measured under basal conditions (Basal) and after addition of oligomycin (ATP, H + leak), FCCP (Max), or actinomycin + rotenone (spare capacity).; n = 8, n = 4, or n = 8 biologically independent mice for 0 (vehicle), 0.3, or 1 mg/kg IACS-010759, respectively. Data analyzed by two-way ANOVA with Dunnett’s Multiple comparison test. Mean ± SE shown. f, Density of intraepidermal nerve fibers (IENF) from mice in (b) assessed by quantifying PGP9.5 and nerve fibers crossing into the hind paw epidermis per length (mm) of the basement membrane. n = 12, n = 8, or n = 8 biologically independent samples for vehicle, 1 mg/kg, or 5 mg/kg IACS-010759, respectively. Data analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test. Mean ± SE shown. g, Immunohistochemistry (IHC) analysis of DRG ATF3 expression (pink) in of mice treated with vehicle, or 1 mg/kg or 5 mg/kg IACS-010759. Positive control = spare nerve injury (SNI) with ATF3 staining. Scale bar = 167.2 µm. Independently repeated three times with similar results. (h) (top) Representative transmission electron microscopy cross sections of the sciatic nerve from mice in (c) after the last dose of vehicle or IACS-010759. Scale bar=2 µm. (bottom) Effects of 5 mg/kg IACS-010759 (n = 131 axons/4 mice) or vehicle (n = 205 axons/4 mice) on myelin. Differences from vehicle group analyzed by a two-tailed Fisher’s exact test; ***p = 0.0003, **p = 0.0031, *p = 0.0447.

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Extended Data Fig. 10 Co-administration of an HDAC inhibitor mitigates the behavioral symptoms of IACS-010759-induced peripheral neuropathy.

a, Spontaneous pain assessed with a Conditioned Place Preference test (Extended Data Fig. 9b) after the last dose of IACS-010759 or vehicle +/− ACY-1215. n = 11, n = 8, or n = 12 biologically independent mice for vehicle, vehicle + ACY-1215, or 1 mg/kg IACS-010759 + vehicle/ACY-1215, respectively. Data were analyzed by a two-way ANOVA. Mean ± SE shown. b, Sensorimotor function of mice in (a) was assessed with a beam walk test after the last dose of IACS-010759 or vehicle +/− ACY-1215. Data represent time to cross the beam. n = 8 or n = 12 biologically independent mice for vehicle + ACY-1215 or all other groups, respectively. Data analyzed by two-way ANOVA with Tukey’s Multiple comparison test. Mean ± SE shown. (c) (left) Representative transmission electron microscopy cross sections of the sciatic nerve from mice in (a) after the last dose of vehicle (top), IACS-010759 (center), or IACS-010759 + ACY-1215 (bottom). Scale bar=2 µm. (Right) Comparison of effects induced by vehicle (n = 184 axons/4 mice), 0.3 mg/kg IACS-010759 (n = 233 axons/4 mice), 1 mg/kg IACS 010759 (n = 158 axons/4 mice), 1 mg/kg IACS-010759 + ACY1215 (n = 201 axons/4 mice), or ACY-1215 (n = 255 axons/4 mice) on myelin. Analysis by two-tailed Fisher’s exact test; **p = 0.0016 vs vehicle; ##p = 0.0041 vs 1 mg/kg IACS-010759.

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Supplementary information

Supplementary Information

Supplementary Tables 1–17, Fig. 1, and thee AML Trial protocol and Solid Tumor trial protocol.

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Yap, T.A., Daver, N., Mahendra, M. et al. Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med 29, 115–126 (2023). https://doi.org/10.1038/s41591-022-02103-8

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