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

Chloroquine Potentiates the Chemotherapeutic Effect of Carboplatin and ATR/Chk1 Inhibitors by Increasing the Replication Stress. (PubMed, Int J Mol Sci) - "We showed that chloroquine sensitized tumor cells (MCF7, SKBR3, HCT116) to drugs (carboplatin, cisplatin) treatment...Treatment with carboplatin and ATR inhibitor (ceralasertib) greatly increased the level of phospho-Chk1 and induced the replication stress, which is consistent with previous studies...Similar results were obtained with the combination of carboplatin and Chk1 inhibitor (prexasertib)...Here, we proposed a novel explanation for the chloroquine ability to potentiate the effect of chemotherapy. The results clearly demonstrated that stress induced by chloroquine is due to its ability to increase the replication stress and to reduce the availability of nucleotides."

Journal • Oncology

CLINICAL ACTIVITY OF ACR-368 IN PATIENTS WITH ENDOMETRIAL CARCINOMA PROSPECTIVLY SELECTED BY ONCOSIGNATURE – A PHASE 2 STUDY - ACR-368-201/GOG3082 (NCT05548296 (ESGO 2026) - P2 | No abstract available

Clinical • Late-breaking abstract • P2 data • Endometrial Cancer • Oncology • Solid Tumor

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

Anticipated Upcoming Milestones (Acrivon Press Release) - "Provide additional update on Arm 1 and initial clinical data from Arm 3 of the ACR-368 Phase 2 trial in mid-2026; Achieve readiness for Phase 3 confirmatory trial for ACR-368 in combination with PD-1 therapy in mid-2026....Report additional ACR-2316 Phase 1 clinical data in weekly and bi-weekly dosing regimens and transition into dose expansion in select tumor types in 1H 2026....Initiate additional internal programs utilizing AP3 platform in 2H 2026."

P1 data • P2 data • Endometrial Cancer • Non Small Cell Lung Cancer • Small Cell Lung Cancer

Acrivon Therapeutics Announces Positive ACR-368 Phase 2b Endometrial Cancer Clinical Data… (Acrivon Press Release) - "Updated interim analysis of data showed a cORR of 67% in BM+ subjects (N=12) with serous EC; Interim analysis across both BM+ and BM- subjects showed a cORR of 52% (N=23) in serous subjects versus 22% (N=37) in non-serous EC subjects; all subjects in this analysis received up to two prior LoT, including chemotherapy and anti-PD-1."

P2b data • Endometrial Cancer

ACR-368: Potential First-in-Class CHK1 / CHK2 Inhibitor (Acrivon Press Release) - "EU Clinical Trial Application for Arm 3 of the ongoing US multicenter, registrational-intent Phase 2b trial in serous subjects with ≤2 prior LoT and without requirement for a tumor biopsy has been submitted, with the selection of more than 20 sites across four major EU countries (Germany, Italy, France, and Spain). Initial patient enrollment in the EU is expected in the first quarter of 2026, with enrollment at previously activated US clinical sites continuing....The company expects to complete enrollment in Arm 3 in the fourth quarter of 2026 (design of up to N=90 subjects, with potential for validation of clinical significance in as few as 40 subjects, including possibility of earlier interim analysis)."

Trial status • Endometrial Cancer

CHK1 inhibition by prexasertib sensitizes cisplatin-resistant malignant tumor cells via checkpoint abrogation and STAT1-driven PD-L1 upregulation. (PubMed, Int Immunopharmacol) - "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."

IO biomarker • Journal • Cervical Cancer • Head and Neck Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • IFNG • PD-L1 • STAT1

Acrivon Therapeutics...announced it will be providing ACR-368 and ACR-2316 clinical data and other updates in January 2026. (The Manila Times) - "Topics will include: Updated interim ACR-368 clinical data from the ongoing registrational-intent Phase 2b study as well as an update on the additional recently initiated tumor biopsy-independent Phase 2b arm, and the planned confirmatory Phase 3 trial; Initial clinical data from the ongoing Phase 1 study of ACR-2316, a potential first- and best-in-class WEE1/PKMYT1 inhibitor, including safety data, dosing regimen, and early clinical activity across AP3-prioritized solid tumor types; Nomination of new preclinical development candidate, including target disclosure, for Acrivon’s AP3-driven cell cycle program."

Clinical data • Pipeline update • Endometrial Adenocarcinoma • Squamous Cell Carcinoma of Head and Neck

Role of DNA damage sensing and TP53 function as modulators of sensitivity to calicheamicin-based antibody-drug conjugates (ADCs) for acute leukemia (ASH 2025) - "Better survival of some patients with the CD33 ADC, gemtuzumab ozogamicin (GO), and the CD22 ADC, inotuzumab ozogamicin (InO), validate these efforts, but these ADCs are ineffective in many others...CLM-induced cytotoxicity was assessed in vitro in the presence/absence of a Mouse Double Minute 2 homolog (MDM2) inhibitor (idasanutlin), Ataxia-Telangiectasia Mutated (ATM) inhibitor (AZD1390, lartesertib), Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (ceralasertib), Checkpoint Kinase 1 and Checkpoint Kinase 1 (Chk1/Chk2) inhibitors (prexasertib, BML-277), and poly(ADP-ribose) polymerase (PARP) inhibitor (veliparib)... Our studies identify ATM, MDM2, and TP53 as key modulators of CLM-induced cytotoxicity in acute leukemia cells. These results support further evaluation of combination therapies with corresponding small molecule inhibitors (currently pursued in patients with other cancers) toward possible clinical testing as novel strategies to increase the efficacy..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Ataxia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Primary Immunodeficiency • CD22 • CD33 • CDKN1A • FBXW7 • TP53

Investigating the role of CDKN2B in glioblastoma (SNO 2025) - "We generated double knockouts of CDKN2A and CDKN2B in M059K cells and obtained modest but significant increases in sensitivity to both the CHK1/2 inhibitor Prexasertib and the WEE1 inhibitor Adavosertib, another inhibitor of the G2/M checkpoint. This demonstrated that the additional loss of CDKN2B along with CDKN2A loss and TP53 mutation was necessary to sensitize these cells to G2/M checkpoint inhibition. This work suggests that inactivation of both CDKN2A and CDKN2B is necessary to accurately model this homozygous deletion."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • CDKN2A • CDKN2B • CHEK2

High-Throughput Drug Repurposing Identifies SN-38 As a Potent Inhibitor of AML with Synergistic Effects in Combination with PARP and BCL-2 Inhibitors for Treating KMT2A-Rearranged Leukemias (ASH 2024) - "Results : High Throughput Drug Screening identified the top five most active FDA-approved drugs across 6 AML cell lines : 1) SN-38 (a topoisomerase I inhibitor and the active metabolite of irinotecan), 2) Triplotide (an NF-κB inhibitor), 3) Mitoxantrone (a topoisomerase II inhibitor), 4) Idarubicin (a topoisomerase II inhibitor), and 5) Bortezomib (a proteasome inhibitor)...Drugs that exhibited greater selectivity, meaning greater responses in KMT2Ar cell lines, included : 1) Ingenol Mebutate (a PKC inhibitor), 2) a BET bromodomain inhibitor, 3) MIK665 (an MCL1 inhibitor), 4) Prexasertib (a CHK inhibitor), and 5) Crenolanib (an FLT3/PDGFR inhibitor)...Moreover, the observed synergy with PARP and BCL-2 inhibitors reveals strategies to overcome AML resistance mechanisms to SN-38. However, rigorous preclinical and clinical studies are essential to validate its efficacy, safety, and optimal dosing regimens."

Combination therapy • IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AFF1 • FLT3 • KMT2A • MLLT3

Investigating the role of CDKN2B in glioblastoma (WFNOS 2025) - "We generated double knockouts of CDKN2A and CDKN2B in M059K cells and obtained modest but significant increases in sensitivity to both the CHK1/2 inhibitor Prexasertib and the WEE1 inhibitor Adavosertib, another inhibitor of the G2/M checkpoint. This demonstrated that the additional loss of CDKN2B along with CDKN2A loss and TP53 mutation was necessary to sensitize these cells to G2/M checkpoint inhibition. This work suggests that inactivation of both CDKN2A and CDKN2B is necessary to accurately model this homozygous deletion."

Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • CDKN2A • CDKN2B • CHEK2

αGal9Ab Treatment As a Novel Therapy for Blood Cancer (ASH 2023) - "Notably, αGAL-9Ab treatment synergized with multiple CHEK1 inhibitorscurrently being tested in phase I or II clinical trials (GDC-0575, Prexasertib and PF477736) to enhance the in vitro killing of human T-ALL, B-ALL, and AML cells. In conclusion, single-agent αGAL-9Ab treatment appears to be cytotoxic against multiple acute leukemia subtypes ( ALs) and its efficacy is enhanced with CHEK1 inhibition. To validate this novel combinatorial approach for treating ALs, additional studies need to be performed to define the mechanisms of action and further pre-clinical experiments will be invaluable in determining the efficacy and safety of these therapies."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • CHEK1 • LGALS9 • MCL1

Combined CHK1 and PD-L1 blockade as a novel therapeutic strategy against stemness and immunosuppression in ovarian cancer. (PubMed, Cancer Immunol Immunother) - "Dual targeting of CHK1 and PD-L1 may improve OC treatment by simultaneously suppressing stemness and enhancing anti-tumor immunity."

IO biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • CD4 • CD8 • CHEK1

Aberrant Splicing in CHEK1 Is a Driver of Megakaryocytic Dysplasia in U2AF1S34F Mutant Myelodysplastic Syndromes (ASH 2024) - "CHK1 inhibitor Prexasertib treatment resulted in a significant increase in the ploidy level of HEL and K562 cells with overexpressed U2AF1S34F...In U2AF1S34 mutant MDS, CHEK1 isoform switching resulted aberrant phosphorylated CHK1 may arrest the cell cycle, with impairing the MK polyploidization and blocking the maturation. Therefore, CHK1 inhibitor can promote U2AF1S34F mutant megakaryocyte maturation and may serve as a novel therapy in MDS."

Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CHEK1 • ITGA2B • U2AF1

Decitabine Synergizes with Replication Checkpoint Inhibitors in TP53-Mutated Acute Myeloid Leukemia (ASH 2024) - "Prior reports suggest that DNA methyltransferase inhibitors (DNMTi), such as decitabine and azacitidine, form covalent DNA-DNMT1 adducts and invoke a DNA damage response (DDR) characterized by activation of the ATR-CHK1 pathway, including in TP53MT AML samples...Similar results were obtained from decitabine (EC50 = 300 ± 100 nM) and ceralasertib (CI 0.54), adavosertib (CI 0.67), MK-8776 (CI 0.52), and prexasertib (CI 0.81) in annexin V assays.These combinations were further evaluated (SubG1 assays) in an isogenic pair of Molm13 and Molm13 TP53-/- cell lines...Combination treatment was antagonistic with ceralasertib (CI 2.2), additive with prexasertib (CI 1.0), and synergistic with adavosertib (CI 0.88).ConclusionsIn multiple cell lines and diverse primary AML samples, decitabine activated the ATR-CHK1 DDR pathway and synergized with ATRi, CHK1/2i, and WEE1i. Amongst these, only the combination of decitabine plus adavosertib exhibited synergy across all three models,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • DNMT1

Mitotic Dysregulation Sensitizes Malignant Stem Cells to CHK1 Inhibition in SF3B1-Mutant Myeloid Neoplasms (ASH 2023) - "In conclusion, we developed a precise gene editing strategy of human HSCs to identify prexasertib as a promising therapy for SF3B1m myeloid neoplasms, and implicate the mitotic function of CHK1 as a SF3B1m sensitivity. The safety and toxicity profiles displayed in early phase clinical trials make prexasertib a suitable agent for further clinical investigation in SF3B1m MDS and its advanced stages."

IO biomarker • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • BUB1B • CD133 • CD34 • CD38 • CDC27 • RUNX1 • SF3B1 • STAG2

ACR-368: Protection of composition-of-matter patent until Oct 2030 (Acrivon Therapeutics) - Corporate Presentation: Protection of patent related to salt form until Apr 2037

Patent • Oncology

FSTL3 is a biomarker of poor prognosis and associated with immunotherapy resistance in ovarian cancer. (PubMed, J Exp Clin Cancer Res) - "FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance. In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance."

Biomarker • IO biomarker • Journal • Fibrosis • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • CD8 • KRAS

Resistance signatures manifested in early drug response across cancer types and species. (PubMed, Cancer Drug Resist) - "Knockout of genes marking resistant states sensitized ovarian cancer cells to Prexasertib... Early cellular transcriptional responses to therapy exhibit key similarities to fully resistant states across different drugs, cancer types, and species. Gene signatures defining these early resistance states have prognostic value in clinical settings."

Journal • Oncology • Ovarian Cancer • Solid Tumor

CHEK1 is a synthetic lethal interactor of FBXO7 in colonic epithelial cells. (PubMed, Mol Ther Oncol) - "Furthermore, combining Prexasertib with 5-fluorouracil, a standard chemotherapeutic agent, produced a synergistic killing effect. These findings establish a novel synthetic lethal relationship between FBXO7 and CHEK1, suggesting that CHEK1 inhibition may provide a targeted therapeutic strategy for CRC patients with FBXO7 deficiencies, and highlighting the broader potential of exploiting SCF complex alterations in CRC therapy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CHEK1 • CUL1

Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer. (PubMed, Cancer Discov) - "Strikingly, three HRP subtypes emerged, marked by unique structural alterations and gene expression patterns, tumor microenvironment interactions, and different chemotherapy responses. Finally, organoid experiments showed subtype-specific sensitivity to CHK1 inhibition, suggesting prexasertib as a potential targeted treatment for most currently untreatable HRP patients."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

ACR-368-201: A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma (clinicaltrials.gov) - P2 | N=353 | Recruiting | Sponsor: Acrivon Therapeutics | Phase classification: P1/2 ➔ P2 | Trial completion date: Dec 2027 ➔ Apr 2027 | Trial primary completion date: Jul 2026 ➔ Oct 2026

Phase classification • Trial completion date • Trial primary completion date • Endometrial Adenocarcinoma • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor

Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids. (PubMed, Exp Mol Pathol) - "The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin...In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993-354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993-354-T-J3 mct-spheroids...Regions of potentiation were evident in the 922,993-354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254-011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence..."

Journal • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Endometrial Serous Carcinoma • Melanoma • Oncology • Solid Tumor • BRCA • LIG3 • MSI • PALB2 • PARP1 • XRCC1