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

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

A phase II study of ACR-368 and low dose gemcitabine combination therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. (ASCO 2025) - P2 | "Since recruitment began 09-25-2024, 5 of planned 43 patients have been enrolled as of 01-22-2025. Clinical trial information: NCT06597565."

Clinical • Combination therapy • IO biomarker • IO Companion diagnostic • Metastases • P2 data • PD(L)-1 companion diagnostic • Head and Neck Cancer • Oncology • Palliative care • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Resistance Signatures Manifested in Early Drug Response in Cancer and Across Species. (PubMed, bioRxiv) - "CRISPR-Cas9 knockout of resistant states' markers increased sensitivity to Prexasertib in ovarian cancer cells. Finally, early resistant state signatures discriminated therapy responders from non-responders across multiple human cancer trials, and distinguished premalignant breast lesions that progress to malignancy from those that do not."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Co-inhibition of Notch1 and ChK1 triggers genomic instability and melanoma cell death increasing the lifespan of mice bearing melanoma brain metastasis. (PubMed, J Exp Clin Cancer Res) - "A therapy with anti-N1/prexasertib could represent a novel treatment strategy, alone or in combination with current treatment regimens, for melanoma brain metastases."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • CHEK1 • NOTCH1

ACR-368, a CHK1/2 Kinase Inhibitor, in Patients With Relapsed or Refractory Desmoplastic Small Round Cell Tumor: Phase I/II Trial Results. (PubMed, JCO Oncol Adv) - "The RP2D of ACR-368 with irinotecan by age group is ACR-368 105 or 150 mg/m2 once on day 1 (>21 years or ≤21 years, respectively) and irinotecan 15 mg/m2 once daily for 5 days in 21-day cycles for both groups. The study met its primary objective to consider ACR-368 and irinotecan promising in DSRCT and, to our knowledge, is the first incorporating a targeted therapy to achieve this magnitude of response."

Journal • P1/2 data • Hematological Disorders • Oncology • Soft Tissue Sarcoma

Acrivon Therapeutics Reports First Quarter 2025 Financial Results and Business Highlights (Yahoo Finance) - "Anticipated Upcoming Milestones: (i) Provide update on registrational-intent trial and confirmatory trial design for ACR-368; (ii) Report initial clinical data from the Phase 1 clinical study of ACR-2316 in the second half of 2025; (iii) Advance a new potential first-in-class cell cycle drug discovery program for an undisclosed target towards development candidate nomination in 2025."

Clinical protocol • P1 data • Pipeline update • Solid Tumor

Enhancing antitumor immunity by targeting cancer associated fibroblasts with radiation and ATM inhibition (ESTRO 2025) - "Cells were treated with radiation (2, 6 or 18 Gy) and inhibitors targeting ATR (VE-822), ATM (AZD1390), CHK1 (LY2606368) and WEE1 (AZD1775). This study demonstrates that combining radiation with ATM inhibition can effectively target CAFs, inducing an IFN-I response. Beyond the well-established radiosensitizing effects of ATM inhibition, our findings reveal a potential novel role for ATM inhibitors in reprogramming NSCLC-CAFs into an immune-activating phenotype. This dual mechanism represents a promising approach to enhance radiotherapy-immunotherapy synergies by reducing the immunosuppressive influences of the tumor microenvironment."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • CDKN1A • CHEK1 • IFNB1

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

CDK2 activation mediates response of acute myeloid leukemia to CHK1, ATR and WEE1 inhibitors (AACR 2025) - "Here we have comprehensively characterized the processes that occur between the interruption of replication checkpoints and leukemic cell death in these sensitive cells versus cells selected for RCM resistance. Using the CHK1 inhibitors MK8776 and prexasertib, ATR inhibitors berzosertib and ceralasertib, and WEE1 inhibitor adavosertib as paradigm drugs, we examined signaling in two AML cell lines, U937 and THP.1, that were selected for CHK1 inhibitor resistance, examined cross-resistance patterns, and assessed the biochemical basis for leukemic cell death. Our findings reveals critical new insights into the factors that influence the response to CHK1 inhibitors in AML. Importantly, we found no evidence of cross-resistance to inhibitors of other replication checkpoint proteins, enabling alternative options."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDC25A • CDK2 • CHEK1 • GNRP • TNFA • TP53

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