Ribonucleotide reductase holoenzyme (RRM1–RRM2 interface) (RNR)

Ribonucleotide reductase (RNR) is a key enzyme that catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleoside triphosphates (dNTPs), the building blocks required for DNA replication and repair [2.1.1, 2.4.3]. The human RNR holoenzyme typically functions as a heterotetramer consisting of two large catalytic subunits (RRM1) and two small regulatory subunits (RRM2 or RRM2B) [2.1.2, 2.2.1]. The RRM1–RRM2 interface is essential for the assembly of the active enzyme complex and the subsequent transfer of a tyrosyl radical from the RRM2 subunit to the RRM1 catalytic site [2.4.3, 3.1.2]. In many types of cancer, RNR is overexpressed to support rapid cell proliferation, making it a significant therapeutic target [2.2.3, 2.3.2]. While traditional inhibitors like hydroxyurea and gemcitabine target the individual subunits or the catalytic process, newer agents like TAS-1553 and COH29 specifically target the RRM1–RRM2 interface [2.4.1, 3.3.1]. By disrupting this protein-protein interaction, these drugs prevent the formation of the active holoenzyme, leading to dNTP depletion, replication stress, and eventual cell death [3.3.3, 3.4.1]. This approach offers a more selective mechanism to overcome resistance associated with conventional RNR-targeted therapies [3.1.3, 3.4.2]. Furthermore, targeting the interface may reduce off-target toxicities compared to non-specific radical scavengers or iron chelators [3.1.2, 3.4.1].

Other names

RRM1-RRM2 complexRibonucleotide reductase complexRibonucleoside-diphosphate reductaseRNR holoenzymeRNR interface

Inhibition of the protein-protein interaction between the RRM1 and RRM2 subunits, which prevents the assembly of the active ribonucleotide reductase holoenzyme and blocks the radical transfer necessary for catalysis.