Targeting OXPHOS de novo purine synthesis as the nexus of
            <i>FLT3</i>
            inhibitor–mediated synergistic antileukemic actions

Zhang, Pu; Brinton, Lindsey T.; Gharghabi, Mehdi; Sher, Steven; Williams, Katie; Cannon, Matthew; Walker, J. T.; Canfield, Daniel; Beaver, Larry; Cempre, Casey B.; Phillips, Hannah; Chen, Xuyong; Yan, Pearlly S.; Lehman, Amy; Scherle, Peggy; Wang, Min; Vaddi, Kris; Baiocchi, Robert A.; Wang, Ruoning; Sampath, Deepa; Alinari, Lapo; Blachly, James S.; Lapalombella, Rosa

doi:10.1126/sciadv.abp9005

Cited by 9 publications

(4 citation statements)

References 60 publications

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“…A previous report using CRISPR/Cas9 screening suggested synergy between DHODH and FLT3 inhibition (32). Using these same CRISPR/Cas9 data, another study demonstrated that a switch from glycolysis to oxidative phosphorylation may represent a metabolic adaptation that could mediate gilteritinib (gilt) resistance (33). Therefore, we investigated the synergy between HOSU-53 and gilt using a modified, more aggressive MOLM-13 model in which treatment started 10 days postengraftment (versus 4 days in all other MOLM-13 CDX studies).…”

Section: Introductionmentioning

confidence: 77%

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Elgamal,

Fobare,

Vibhute

et al. 2024

JCI Insight

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Acute myeloid leukemia (AML) represents the most commonly diagnosed and lethal adult leukemia, with a 5-year survival of less than 15% in patients over the age of 60 (1, 2). AML originates from a leukemia-initiating hematopoietic stem cell and is characterized by uncontrolled proliferation of dysfunctional, immature hematopoietic myeloid cells (blasts). AML-initiating cells have features that resemble normal hematopoietic stem cells and are highly immune suppressive, making it quite challenging to treat with either targeted or immune-based therapies (outside of allogeneic stem cell transplant). Until recently, effective therapies for AML were limited to intensive chemotherapy followed by allogeneic stem cell transplant, which provided curative potential for a minority of patients. More recently, several therapies targeting select mutations, including IDH1 (ivosidenib) (3), IDH2 (enasidenib) (4), and FLT3 (gilteritinib) (5), have been approved for AML treatment and demonstrate a unique differentiating phenotype. By differentiating early AML progenitor cells, these therapies may further separate their phenotype from normal hematopoietic cells and in some cases can promote durable remissions. However, these targeted therapeutics are limited to AML patients with IDH1, IDH2, or FLT3 mutations, and resistance mechanisms have been reported (6, 7). Another example of mutation-specific, targeted differentiation therapy is all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) AML subtype. Despite the high response rate, there is a lack of durable response in most patients in the absence of combination therapy (8-10). This collective experience suggests that successful therapy will involve differentiation agents that can be used in a broader AML population and identifying combination strategies likely to result in durable remissions. The need for combination strategies is supported by murine model data of AML, where a combination of differentiation and targeted therapies is required to eliminate clonal AML stem cells (11). Broadly affecting AML with differentiation therapy will require a therapeutic target that is effective in AML subtypes independent of mutation subtype.One such target for broad differentiation of AML cells demonstrated by Sykes and Scadden et al. ( 12) and later corroborated by others is dihydroorotate dehydrogenase (DHODH) (13-15). DHODH is a mitochondrial membrane flavoprotein that catalyzes the rate-limiting step of the de novo pyrimidine nucleotide biosynthesis pathway (16,17). DHODH catalyzes the oxidation of dihydroorotate (DHO) to orotate, which is further converted downstream by uridine monophosphate synthetase to uridine monophosphate (18, 19), the biosynthetic precursor of thymidine and cytidine (20). Rapidly proliferating cells and most cancer cells rely predominantly on this de novo synthesis pathway (20) as opposed to the salvage pathway, which re-cycles degraded intracellular nucleic acids (17) or shuttles extracellular nucleosides using nucleoside transporters (12,17,20). Th...

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Section: Introductionmentioning

confidence: 77%

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Elgamal,

Fobare,

Vibhute

et al. 2024

JCI Insight

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“…Notably, previous work done in AML cell lines that show resistance to chemotherapy also show increased mitochondrial mass and increased OxPhos. 56 …”

Section: Resultsmentioning

confidence: 99%

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Sexauer,

Alexe,

Gustafsson

et al. 2023

Blood Advances

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Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.-

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“…Chemotherapy-resistant AML cells displayed a high oxidative phosphorylation status . Targeting mitochondrial protein synthesis and electron transfer induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of chemotherapy. − HsClpP chemo-activation by ONC201 or ONC212 has been proven as a promising approach that can be used against AML. , However, the antileukemic effects of ONC201 or ONC212 monotherapy is limited in AML. , It seems that more efficient HsClpP agonists can better elucidate the therapeutic value of targeting HsClpP in AML. Thus, a novel class of HsClpP agonists is designed and synthesized using a ring open strategy based on the lead compound 1 , which is designed through a position shift strategy based on the imipridone ONC201 .…”

Section: Discussionmentioning

confidence: 99%

Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity

Xiang,

Dai,

Luo

et al. 2024

J. Med. Chem.

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The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC 50 = 0.79 ± 0.03 μM) and antitumor activity in vitro (IC 50 = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

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Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions

Cited by 9 publications

References 60 publications

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

DHODH: a promising target in the treatment of T-cell acute lymphoblastic leukemia

Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity

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