Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes—A novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies

Bantia, Shanta; Parker, Cynthia; Upshaw, Ramanda; Cunningham, Amanda; Kotian, Pravin L.; Kilpatrick, J. Michael; Morris, Phillip; Chand, Pooran; Babu, Y.S.

doi:10.1016/j.intimp.2010.04.009

Cited by 32 publications

(20 citation statements)

References 25 publications

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“…Imm-H and DADMe-ImmH show low toxicity in animal studies. ImmH is in clinical trials for T-cell malignancies under the name of Forodesine ™ , and DADMe-ImmH is in clinical trials for gout under the name BCX4208 (78, 79). …”

Section: Transition-state Structures and Analogsmentioning

confidence: 99%

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Schramm

2011

Annu. Rev. Biochem.

202

235

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Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits (a) the design of transition-state analogs as powerful enzymatic inhibitors, (b) exploration of protein features linked to transition-state structure, (c) analysis of ensemble atomic motions involved in achieving the transition state, (d) transition-state lifetimes, and (e) separation of ground-state (Michaelis complexes) from transition-state effects. Transition-state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein’s dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states.

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Section: Transition-state Structures and Analogsmentioning

confidence: 99%

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Schramm

2011

Annu. Rev. Biochem.

202

235

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“…14 Syntheses of the enantiomers of the two clinical leads, Forodesine 15–18 and Ulodesine, 19–21 have been reported together with their biological activity (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Tight binding enantiomers of pre-clinical drug candidates

Evans

Cameron

Luxenburger

et al. 2015

Bioorganic & Medicinal Chemistry

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MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of E. coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2 respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.

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“…Immucillins are powerful picomolar transition-state analogue inhibitors of both human and Plasmodium PNPs [16]. They are orally available and of low toxicity to animals and humans [17]. We selected BCX4945 as an inhibitor for in vivo trials because of its high affinity for both host and parasite PNPs (7 pM and 890 pM K d values, respectively) [18].…”

Section: Resultsmentioning

confidence: 99%

Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

et al. 2011

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Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.

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Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes—A novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies

Cited by 32 publications

References 25 publications

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Enzymatic Transition States, Transition-State Analogs, Dynamics, Thermodynamics, and Lifetimes

Tight binding enantiomers of pre-clinical drug candidates

Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

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