DEL-22379

DEL-22379 is an inhibitor of the dimerization of ERK with IC50 values ranging from 150-400 nM regardless of genotypes in oncogenic cells [1].

As an spatial regulator of ERK signals, ERK dimerization is essential. Impeding ERK dimerization can result in the impeding of ERK signals’ extranuclear component and hence result in curtailing tumor development and cellular transformation [1].

In HEK293 cells, DEL-22379 abolished EGF-stimulated ERK dimerization. In these cells, the EGF-induced co-immunoprecipitation of hemagglutinin- or FLAG epitopes- tagged ectopic ERK2 molecules, was abolished by DEL-22379 with an IC50 value of ~0.5 µM. In both assays, the inhibition of DEL-22379 to ERK dimerization was not associated with ERK phosphorylation. In the cytoplasm of EGF-stimulated HeLa cells, ERK dimerization was prominent, but previous treatment with DEL-22379 also resulted in no detected ERK dimmers [1].

In nude mice with some of the aforementioned tumor cell lines, DEL-22379 at a dose of 15 mg/kg inhibited ERK dimerization evidently in xenografted tumors and in liver extracts. DEL-22379 inhibited the tumor progression of A375 cells (BRAF mutant) markedly. Activated-RAS-driven tumors were very sensitive to DEL-22379. Data indicated that tumorigenesis had greater requirements for ERK dimerization than for proliferation. In tumors, treatment with DEL-22379 resulted in extensive mucinous differentiation and cell death [1].

Reference:
[1].  Herrero A, Pinto A, Colón-Bolea P, et al. Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer cell, 2015, 28(2): 170-182.

Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.[Pubmed:26267534]

Cancer Cell. 2015 Aug 10;28(2):170-82.

Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.

Targeting RAS-mutant cancers: is ERK the key?[Pubmed:26858988]

Trends Cancer. 2015 Nov 1;1(3):183-198.

The three RAS genes comprise the most frequently mutated oncogene family in cancer. With significant and compelling evidence that continued function of mutant RAS is required for tumor maintenance, it is widely accepted that effective anti-RAS therapy will have a significant impact on cancer growth and patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, a clinically effective anti-RAS drug has yet to be developed. With the recent renewed interest in targeting RAS, exciting and promising progress has been made. In this review, we discuss the prospects and challenges of drugging oncogenic RAS. In particular we focus on new inhibitors of RAS effector signaling and the ERK mitogen-activated protein kinase cascade.

DEL-22379 is an ERK dimerization Inhibitor. DEL-22379 readily binds to ERK2 with a Kd estimated in the low micromolar range, though binding is detectable even at low nanomolar concentrations. ERK2 dimerization is progressively inhibited with an IC50 of ~0.5 μM.

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