prexasertib (ACR-368) / Pfizer, SOM Biotech, Ewha Womans University, Acrivon Therap - LARVOL DELTA

Integrative Spatial and Single-Cell Transcriptomics Uncovers Therapeutically Actionable Pathways in Embryonal Tumors with Multilayered Rosettes (EANO 2026) - "Our study highlights DNA damage response and anti-apoptotic pathways as actionable therapeutic targets in ETMRs and supports the potential use of DNA damage pathway inhibitors, alone or in combination, as a novel treatment strategy for this aggressive pediatric brain tumor."

Embryonal Tumor • Oncology

Discovery of potent, selective, and orally bioavailable monocyclic pyridine-based PKMYT1 inhibitors that synergize with CHK1 inhibition in replication-stressed cancer cells. (PubMed, Bioorg Med Chem Lett) - "Furthermore, the combination of compound 18 with the CHK1 inhibitor prexasertib demonstrated robust synergistic antitumor activity against triple-negative breast cancer (TNBC) and ovarian cancer cells. Collectively, compound 18 emerges as a promising preclinical lead candidate for targeted cancer therapy."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CCNE1 • CDK1 • PKMYT1

A phase I/II study of prexasertib in combination with irinotecan in patients with relapsed/refractory desmoplastic small round cell tumor and rhabdomyosarcoma. (ASCO 2022) - P1/2 | "The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated."

Clinical • Combination therapy • P1/2 data • Fatigue • Hematological Disorders • Neutropenia • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer. (PubMed, Sci Transl Med) - P2 | "Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models...BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC."

Biomarker • Journal • Ataxia • Bloom Syndrome • Breast Cancer • Immunology • Metabolic Disorders • Movement Disorders • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Primary Immunodeficiency • Solid Tumor • ATR • BLM • BRCA • CCNE1

Integrative Bioinformatics Identification of Baicalein as a Phytochemical Inhibitor of CHEK1 in Serous Ovarian Cancer: A Multi-Stage In Silico Drug Discovery Approach. (PubMed, Pharmaceuticals (Basel)) - "Baicalein exhibited the highest binding affinity (-9.334 kcal/mol), surpassing Prexasertib (-7.2 kcal/mol). MD simulations confirmed complex stability, and ADMET profiling demonstrated favorable drug-likeness with zero Lipinski violations. CHEK1 is established as a validated therapeutic target in SOC, and Baicalein is identified as a computationally superior natural lead compound, warranting experimental validation in ovarian cancer models."

Journal • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CHEK1

Chk1 inhibition emerges as the most effective partner for PARP inhibition in BRCA-proficient pancreatic cancer. (PubMed, Discov Oncol) - "Combined PARP and Chk1 inhibition exerts potent antitumor activity both in vitro and in vivo in pancreatic cancer models, including BRCA-proficient tumors."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • ANXA5 • BRCA • BRCA1 • BRCA2 • RRM1

Small molecule drug screening, chemoinformatics and integrative transcriptomics identify targetable MYC-dependent therapeutic vulnerabilities in high-risk medulloblastoma (ISPNO 2026) - "Inhibition of AURKA (with alisertib) and CHEK1 (with prexasertib) was found to significantly extend survival and reduce tumour burden. Our findings demonstrate dual-AURKA/CHEK1 inhibition exerts a robust anti-tumour effect in MYC-MBG3 that warrants clinical evaluation. Importantly, we present an integrative screening pipeline which encompasses human tumour analysis and avatar-based screening to uncover actionable therapeutic vulnerabilities in MYC-MBG3, which is readily adaptable to other high-risk medulloblastoma disease features."

Brain Cancer • Medulloblastoma • Solid Tumor • MYC • PLK1

ATR Targetting Enhances Craniospinal Irradiation Response in SHH-Activated TP53-Mutant Medulloblastoma (ISPNO 2026) - "SHH-3/TP53mut MED813FH and MED314FHmCL PDOX mice were treated with fractionated craniospinal irradiation (CSI) at onset of clinical tumour symptoms using a 5-days-on, 2-days-off treatment cycle where mice received 10 x 1 Gy fractions (10 Gy total) either alone or in combination with concurrent prexasertib (CHKi), ceralasertib (ATRi) or second-generation ATRi, elimusertib. Using gold standard PDOX models and methodology with high clinical fidelity, we demonstrate that ATR inhibitors significantly enhance survival when combined with CSI. These data provide a strong preclinical rationale for the clinical translation of ATR inhibitors for patients with SHH-3/TP53mut MB, a population with significant unmet clinical need."

Brain Cancer • Medulloblastoma • Solid Tumor • MYC • TP53

Dangerous liaisons: Promiscuous inhibition of CHK1 and AMPK is a lethal affair for cancer cells. (PubMed, Cell Chem Biol) - "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."

Journal • Oncology • AMPK • CHEK1

Combination of CHK1 and CHK2 inhibitors exerts synergistic antitumor effects against neuroblastoma cells. (PubMed, Pediatr Res) - "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."

Journal • Neuroblastoma • Oncology • Solid Tumor • CASP3 • MYCN • RPA2

The CHK1 inhibitor Prexasertib is effective against in vitro models of aggressive thyroid carcinomas with defective p53 function. (PubMed, Front Endocrinol (Lausanne)) - "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."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CHEK2

PHKG2 confers resistance of ESCC to cisplatin and enhances CXCL8-dependent immunosuppression to exacerbate tumorigenesis. (PubMed, Cell Death Dis) - "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."

Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CXCL8 • IGF2BP3 • PHKG2

Anticipated Upcoming Milestone (The Manila Times) - “Achieve readiness for Phase 3 confirmatory trial for ACR-368 in combination with PD-1 therapy by mid-2026”

New P3 trial • Endometrial Cancer

ACR-368-201: A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma (clinicaltrials.gov) - P2 | N=401 | Recruiting | Sponsor: Acrivon Therapeutics | Trial completion date: Apr 2027 ➔ Nov 2027 | Trial primary completion date: Oct 2026 ➔ May 2027

P53mut • Trial completion date • Trial primary completion date • Endometrial Adenocarcinoma • Endometrial Cancer • Oncology • Solid Tumor • TP53

ACR-368: CHK1 / CHK2 Inhibitor (The Manila Times) - "...presented interim analysis of the ongoing, multi-arm, registrational intent Phase 2b study across both OncoSignature-positive (BM+) and BM- endometrial cancer (EC) subjects showed a confirmed overall response rate (cORR) of 52% (N = 23) in serous EC subjects versus an ORR of 22% (N = 37) in non-serous EC subjects, with all subjects having received up to two prior lines of therapy (LoT), including chemotherapy and anti-PD-1...Anticipated Upcoming Milestones - A prespecified simultaneous interim analysis and data update from both all-comer (biopsy-independent) serous EC arms of the ACR-368 Phase 2b study in second half of 2026; Based on interim data read-out, complete enrollment of the registrational intent all-comer (biopsy-independent) serous EC Arm 3 or Arm 4 by fourth quarter of 2026"

Enrollment status • P2b data • Endometrial Cancer

ACR-368-201: A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma (clinicaltrials.gov) - P2 | N=353 | Recruiting | Sponsor: Acrivon Therapeutics | N=72 ➔ 353

Enrollment change • Endometrial Adenocarcinoma • Endometrial Cancer • Oncology • Solid Tumor

The cytotoxic effect of prexasertib is a consequence of dual inhibition on both CHK1 and AMPK. (PubMed, Cell Chem Biol) - "Exonuclease 1 (Exo1) hyperactivation following combined AMPK and CHK1 inhibition may represent a critical mechanism underlying Prex sensitivity. Our findings revealed an additional role of Prex in AMPK regulation and elucidated the functional significance of AMPK inhibition in CHK1 inhibitor-induced cell death."

Journal • AMPK • CHEK1 • STK11

Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines (AACR 2024) - "The potential of novobiocin to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells and tumor-bearing mice and in Phase 1 clinical trials with cyclophosphamide or cisplatin...Potentiation of the topoisomerase II inhibitors doxorubicin (DOX) and etoposide by the POLθ inhibitors ART-558 or RP6685 was observed in spheroids grown from the serous endometrial adenocarcinoma 922993-354-T-J3, which has ATM and BRCA2 variants...Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922993-354-T-J3 complex spheroids...KRAS G12D inhibitor MRTX-133 cytotoxicity against 186277-243-T-J2 colon adenocarcinoma with the KRAS G12D variant was potentiated by either ART-558 or RP6685. Potential combinations to advance into in vivo studies will be presented."

Late-breaking abstract • Preclinical • Tumor cell • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Endometrial Adenocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRCA • BRCA2 • KRAS • LIG3 • PALB2 • POLQ • XRCC1

Synergistic anticancer activity of ciclopirox and prexasertib in non-small cell lung cancer cells (AACR 2026) - "Taken together, the results indicate that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells. Our finding suggests that combination of CPX and PRE may represent a novel therapeutic approach for NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BIRC5 • CASP3 • CASP8 • CDC25B • CDC25C • CDK2 • CDK4 • CDK6 • FADD • GNRP

ACR-368 synergizes with PD-L1 blockade by coordinated activation of adaptive and innate immunity pathways to achieve robust anti-tumor efficacy (AACR 2026) - "ACR-368 synergizes with PD-L1 blockade by activating adaptive and innate immune pathways, resulting in potent tumor regression and durable immune memory. These data provide a strong mechanistic rationale for clinical evaluation of ACR-368 in combination with ICIs in tumors selected for sensitivity to these agents."

Clinical • IO biomarker • Late-breaking abstract • Endometrial Cancer • Oncology • Solid Tumor • CD4 • CD8

Potent synergy between CHK1/2 inhibitor ACR-368 and the ADC payload topoisomerase I inhibitor: Rationale for ADC + ACR-368 combination therapy (AACR 2026) - "Consistent with this, treatment with the potent, selective CHK1/2 inhibitor ACR-368 combined with irinotecan has demonstrated encouraging clinical activity in heavily pretreated patients with sarcomas who had progressed on prior irinotecan therapy. Synergy was observed in both Topo I-sensitive and -resistant lines, supporting the potential to overcome resistance to Topo I inhibitor-based ADCs. To elucidate the pathway mechanisms underlying Topo I inhibitor sensitivity and resistance and the potent, synergistic activity with ACR-368, results from our AP3 Generative Phosphoproteomics approach applied to endometrial cancer will be presented.Combined, these findings demonstrate that CHK1/2 inhibition with ACR-368 synergizes with Topo I inhibitors to enhance cytotoxicity and overcome resistance mechanisms, supporting a mechanistically rational combination strategy with potential to improve the therapeutic benefit of Topo I inhibitor-based ADC therapies."

ADC • Combination therapy • Endometrial Cancer • Oncology • Sarcoma • Solid Tumor

Acrivon to Highlight Preclinical Data with Three Posters at AACR Demonstrating Strong ACR-368 and ACR-2316 Synergies with Immune Checkpoint Inhibitors and ADC Payloads, Revealing Broad Clinical Development Opportunities (GlobeNewswire) - "Potent preclinical efficacy with durable immune memory observed in combinations of either ACR-368 or ACR-2316 with anti-PD-L1 and strong synergy of ACR-368 with Topoisomerase 1 (Topo 1) inhibition. Data supports potential for frontline clinical combinations of ACR-368 and ACR-2316 with immune checkpoint inhibitors and of ACR-368 with Topo 1 antibody-drug conjugates (ADCs)."

Preclinical • Solid Tumor

A novel triple combination therapy in small cell lung cancer targeting DNA damage repair as a mechanism of resistance (AACR 2025) - "SCLC is notorious for its response to standard etoposide-platinum doublet therapy; initially responsive, it almost always relapses and no longer responds to first-line treatments...For our experiments, we added prexasertib to our prior combination of imipridone ONC201 (dordaviprone) and small molecule lurbinectedin, previously shown to be synergistic. Prexasertib is a dual inhibitor of Chk1 and 2, protein kinases in the DDR pathway that regulate downstream cell cycle checkpoint (CCC) proteins particularly implicated in G1/S transition and G2 entry. Synergy scores and western blot data from experiments in four cell lines (H1048, H1882, H1105, H1417) point to the role of the DDR-CCC pathway in SCLC treatment resistance and offer a novel treatment modality for testing in vivo, with the ultimate view to progress into the clinic."

Combination therapy • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CHEK1

Decitabine (DAC) induces a DNA damage response (DDR) and synergizes with replication checkpoint inhibitors in acute myeloid leukemia (AML) (AACR 2025) - "(nM)Molm13 (TP53WT)Molm13 (TP53-/-)U937 (TP53G187fs*/-)KG1a (TP53V225fs*/-)Primary AML (TP53WT orTP53MT)UnitsDecitabineDNMT16.25 – 20025 ± 11350 ± 260310 ± 1806.1 ± 1.6NDEC50, nM (mean, SD)CeralasertibATR250 – 5000.93 (0.66 – 1.24)0.90 (0.84 – 0.96)0.15 (0.08 – 0.21)0.74 (0.63 – 1.02)0.66 (0.43 – 2.43)CI with decitabine (median, IQR) CamonsertibATR10 – 1000.27 (0.19 – 0.59)0.24 (0.22 – 0.34)0.34 (0.21 – 0.39)NDNDPrexasertibCHK1/21.0 – 6.00.89 (0.82 – 1.06)0.78 (0.68 – 0.90)0.95 (0.93 – 1.08)ND0.88 (0.29 – 1.28)MK-8776CHK1250 – 1,0000.57 (0.48 – 0.80)0.76 (0.73 – 1.19)0.89 (0.57 – 1.39)NDNDRabusertibCHK1600 – 1,000NDNDND0.51 (0.48 – 0.56)NDAdavosertibWEE1100 – 4000.70 (0.63 – 1.11)0.99 (0.78 – 1.14)0.67 (0.60 – 0.74)0.67 (0.37 – 0.93)0.65 (0.43 – 0.88)Table 1. U937 data were replicated using annexin V. Prexasertib showed no activity in KG1a cells (suggesting drug efflux) requiring the use of the alternate CHK1 inhibitor, rabusertib. Abbreviations: ATR,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ANXA5 • ATR • DNMT1

Combination of carboplatin and CHK1 inhibition to overcome platinum resistance in high grade serous ovarian cancer (AACR 2025) - "The CHK1 inhibitor, prexasertib, demonstrated a synergistic effect when used in combination with carboplatin, correlating with an expected increase in DNA damage and p-CHK1 S317. The use of CHK1 inhibitors with platinum may be a new treatment strategy in platinum resistant HGSOC."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor