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

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) - "Abstract is embargoed at this time."

Clinical • Late-breaking abstract • Oncology

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

ACR-368-201: A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma (clinicaltrialsregister.eu) - P1/2 | N=48 | Not yet recruiting | Sponsor: Acrivon Therapeutics Inc.

New P1/2 trial • Endometrial Adenocarcinoma • Endometrial Cancer • Oncology • Solid Tumor

Overcoming acquired doxorubicin resistance of ovarian carcinoma cells by verapamil‑mediated promotion of DNA damage‑driven cytotoxicity. (PubMed, Int J Oncol) - "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."

Journal • Oncology • Ovarian Cancer • Solid Tumor • ABCB1 • RAC1

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 | "BM-negative (BM-) EC subjects are offered ACR-368 with ultra-low dose gemcitabine (ULDG) given as a sensitizer.Methodology This open-label Phase 2 multi-center trial is enrolling subjects with relapsed EC (serous, clear-cell, carcinosarcoma, and high-grade endometrioid adenocarcinoma). Treatment was well tolerated with manageable transient, mechanism-based hematological adverse events.Conclusion Given these promising results, particularly in serous EC, Arm 3 has been initiated evaluating ACR-368 with ULDG in biomarker-unselected serous EC subjects, who have received ≤2 prior LoT. The study is being expanded to >20 EU sites."

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

Acrivon Therapeutics to Present at the TD Cowen 46th Annual Health Care Conference (Acrivon Press Release) - "Acrivon is currently advancing its lead program, ACR-368 (also known as prexasertib), a selective small molecule inhibitor targeting CHK1 and CHK2 in a potentially registrational Phase 2 trial for endometrial cancer. The company has received Fast Track designation from the Food and Drug Administration, or FDA, for the investigation of ACR-368 as a monotherapy based on OncoSignature-predicted sensitivity in patients with endometrial cancer."

Clinical • Endometrial Adenocarcinoma

Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors. (PubMed, Cell Death Dis) - "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."

Journal • Neuroblastoma • Oncology • Sarcoma • Solid Tumor • RRM2

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

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