prexasertib (ACR-368)

In this issue of Cell Chemical Biology, Guo et al.1 reveal that the Checkpoint kinase 1 (CHK1) inhibitor Prexasertib moonlights as an AMP-activated protein kinase (AMPK) inhibitor that primes cancer cells for destruction. This off-target synergy highlights that serendipitous promiscuity can supercharge the efficacy of some "selective" kinase inhibitors.

Combined CHK1/CHK2 inhibitor therapy shows a synergistic anti-tumor effect against neuroblastoma cells. Combination therapy impairs DNA damage response pathways and drives accelerated cell cycle progression in neuroblastoma cells. Combination therapy increases DNA damage, replication stress, and apoptosis marker expression. Combined CHK1/CHK2 inhibition holds therapeutic potential for the treatment of neuroblastoma.

Recently, we demonstrated that the response to Lenvatinib is associated with alterations in TP53 gene or protein. Moreover, Doxorubicin potentiated the Prexasertib effects in p53-defective thyroid cancer cells, yet at the lowest doses. This study unravels the potential of Prexasertib as a novel treatment option for aggressive thyroid cancers p53-defective and poorly responsive to tyrosine kinase inhibitors.

Significantly, pharmacological inhibition of PHKG2 using prexasertib notably curtails ESCC cell proliferation and enhances cisplatin sensitivity. This study underscores the promising potential of targeting PHKG2 as a therapeutic approach to overcome cisplatin resistance in ESCC.

P2, N=401, Recruiting, Acrivon Therapeutics | Trial completion date: Apr 2027 --> Nov 2027 | Trial primary completion date: Oct 2026 --> May 2027

P2, N=353, Recruiting, Acrivon Therapeutics | N=72 --> 353

P2, N=72, Recruiting, Acrivon Therapeutics | N=48 --> 72

P1/2, N=48, Not yet recruiting, Acrivon Therapeutics Inc.

A2780ADR cells revealed cross‑resistance to multiple compounds, including anticancer drugs [cisplatin (CisPt) and etoposide (Eto)] and DNA repair/DNA damage response (DDR) inhibitors (olaparib, niraparib, entinostat, prexasertib and rabusertib). However, combination treatment with Doxo and Ver also increased the cytotoxic response of non‑malignant murine cardiomyocytes, murine embryonic stem cells and human induced pluripotent stem cells. Taken together, the present study suggested inhibition of MDR1‑mediated Doxo efflux by Ver a useful approach to overcome acquired drug resistance of A2780ADR cells by stimulating DDR‑related cytotoxicity, yet at the price of a potentially increased risk of normal tissue toxicity.

We identified strong synergism for combined RRM2-CHK1 inhibition using the iron chelator triapine and prexasertib respectively. We confirm drug synergism in vivo in a NB zebrafish xenograft model, further underscoring the broad clinical potential of combinatorial RRM2-CHK1 inhibition. Altogether, this study paves the way for further preclinical testing of second generation RRM2 and CHK1 inhibitors such as TAS1553 and SRA737 in neuroblastoma and sarcomas.

Co-treatment with interferon-γ further amplified PD-L1 and γH2A.X expression, highlighting a link between CHK1 inhibition, DNA damage, and immune checkpoint modulation. These findings suggest that Prexasertib not only enhances the cytotoxic effects of cisplatin but also influences immune signaling, providing a mechanistic rationale for future exploration of combined DNA damage response inhibition with immune checkpoint blockade.

Dual targeting of CHK1 and PD-L1 may improve OC treatment by simultaneously suppressing stemness and enhancing anti-tumor immunity.