idasanutlin (RG7388) / Roche - LARVOL DELTA

Profiling drug sensitivity in CLL B cells after BTK inhibitor progression using a novel drug panel (ASH 2025) - " Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other)...We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p -values <0.05 except for GTE which was not significant, Mann-Whitney U test)... Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • AXL • BCL2 • STAT6 • TP53

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

PPM1D mutations confer resistance to venetoclax in pre-leukemic and AML populations (ASH 2025) - "In long-term co-culture assays,PPM1Dmut cells were competitively enriched, compared to WT cells upon exposure to eitherchemotherapy (Ara-C or 5-FU) or VEN...VEN combined with either small molecule PPM1D (GSK-2830371) or MDM2inhibitors (RG-7388) showed promising efficacy against PPM1Dmut, but were ineffective against TP53KOcells. In contrast, VEN + MCL1 inhibitor (S63845) was highly cytotoxic and efficacious across all genotypestested, including both PPM1Dmut and TP53KO cells...PPM1Dmutlikely arises in pre-leukemic or leukemic cells selected toexpand during VEN exposure. Resistance to VEN mediated by PPM1D abnormalities appeared to be TP53dependent and alleviated by combining VEN with MCL1 inhibition, which may also have clinical rationalein pts harboring concurrent PPM1D and TP53 mutant disease."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • FLT3 • KRAS • PPM1D • PTPN11

Idasanutlin in Combination with Chemotherapy or Venetoclax in Pediatric and Young Adult Patients with Relapsed/Refractory Solid Tumors (iMATRIX Idasa): Results of a Phase I/II, Multicenter, Multi-arm Study. (PubMed, Target Oncol) - P1/2 | "The safety profile and tolerable exposure of idasanutlin in pediatrics was similar to that reported in adults. Limited clinical activity was observed in patients with solid tumors. On the basis of the negative benefit-risk assessment, the study was terminated, and the overall pediatric development program for idasanutlin was discontinued."

Journal • P1/2 data • Febrile Neutropenia • Hematological Disorders • Neuroblastoma • Neutropenia • Oncology • Pediatrics • Solid Tumor • Thrombocytopenia

Balancing cell cycle arrest and immune activation: A synergistic window for idasanutlin and anti-PD-1 therapy in a syngeneic mouse model. (PubMed, Biomed Pharmacother) - "High doses of idasanutlin decreased the proliferation of T cells and depleted T cell numbers within the lymphocyte population, as we show in vitro and in vivo. These findings suggest that low doses of MDM2 antagonists may enhance immunotherapy, while higher doses could interfere with immunotherapy by p53-mediated cell cycle arrest and decreasing the proliferation of the immune cells."

IO biomarker • Journal • Preclinical • Oncology • CDKN1A

T-prolymphocytic leukemia(T-PLL) – What are recent improvements? (DGHO 2025) - "With the aim to further improve clinical outcomes, a prospective phase-II trial was conducted by the German CLL Study group using an induction therapy with fludarabine, cyclophosphamide and mitoxantrone (FMC) followed by alemtuzumab consolidation therapy...CIBMTR Data of 266 patients with T-PLL demonstrated a 4-year disease-free survival (DFS) of 25.7% and OS of 30.0%.There are recent clinical pilot data derived from drug screening efforts that provide valuable insights: venetoclax, HDAC-inhibition plus idasanutlin (MDM2 antagonist, activation of p53), and drugs targeting autophagy (thapsigargin and bafilomycin A1), nuclear export (selinexor) or inhibitor of apoptosis proteins (IAPs; birinapant). Valuable trial data teach us on the limited applicability of pre-clinical results, i.e. the limited efficacy of venetoclax+ibrutinib or of itacitinib + alemtuzumab.Overall, responses after induction therapy remain dissatisfactory as most patients relapse even after a CR..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Prolymphocytic Leukemia

INVESTIGATION OF COMBINING MDM2 INHIBITORS WITH DR5 AGONISTS FOR BONE SARCOMA TREATMENT (CTOS 2025) - P2 | "RG7388 is cytotoxic and upregulates DR5 in bone sarcoma cell lines. Combining this agent with novelDR5 agonists may enhance cell killing and potentially survival outcomes. The phase 2 clinical trial of INBRX-109 in unresectable or metastatic conventional chondrosarcoma patients (ClinicalTrials.gov Identifier: NCT04950075) has an estimated primary completion date of September 2025."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CASP7 • CDKN1A • MDM2 • TNFRSF10B

Broadening Degrader Therapeutics: Keap1 PROTACs, Antimalarial Hybrids, and PLK1 Inhibition of NLRP3 Inflammasomes. (PubMed, ACS Med Chem Lett) - "Keap1-based degraders eliminate oncogenic KRAS and androgen receptor in cancer, antifolate-idasanutlin hybrids degrade Plasmodium falciparum DHFR-TS to overcome antifolate resistance, and PLK1 inhibition suppresses NLRP3 inflammasome activation to improve cardiac outcomes. Together, these innovations expand degrader and kinase-targeting strategies into oncology, infectious disease, and inflammatory cardiology."

Journal • Cardiovascular • Infectious Disease • Oncology • Targeted Protein Degradation • AR • DHFR • KEAP1 • KRAS • NLRP3 • PLK1

ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies (ASH 2024) - P1 | "Previous studies have shown in vitro activity in acute myeloid leukemia both alone and in combination with decitabine...Activity of ASTX295 was compared with AMG232 and Idasanutlin...ASTX295 in combination with the specific BCL2 inhibitor Venetoclax in the GRANTA519 cell line (CI value 0.2) and KARPAS384 (CI value 0.4) demonstrated strong synergy, despite as monotherapy resulting in <50% fall in viability...ASTX295 like other MDM2i showed synergy with BCL2i in DLBCL and MCL models. ASTX295 induced multiple forms of PCD; the precise form of non-caspase dependent PCD remains under investigation."

IO biomarker • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • ANXA5 • CDKN1A

Navtemadlin, a Novel MDM2 Inhibitor, Potentiated Venetoclax-Induced Antitumor Efficacy in TP53 Wild-Type Acute Myeloid Leukemia (AML) (ASH 2023) - "A proof-of-concept study with idasanutlin (idasa), a first-generation MDM2 inhibitor and ven demonstrated manageable safety and encouraging efficacy in relapsed/refractory AML patients (Daver et al. Nvtm, a potent second-generation MDM2 inhibitor, rapidly restored p53 function, induced apoptosis in p53WT AML MOLM-13 by impeding cell cycle, viability, clonogenicity potential, and reducing both glycolysis and oxidative phosphorylation. Nvtm combined with ven significantly enhanced these effects. Importantly, this combination blocked stromal cell-mediated (contact and soluble factors) cytoprotection."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IL6 • TP53

Idasanutlin and Navitoclax Induce a Synergistic p53-Dependent Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "Venetoclax showed an additive benefit in 3 lines, but was only synergistic in 1 of 5 lines tested...We also evaluated ruxolitinib in combination with idasanutlin, as recent work has shown overlapping responses to inhibitors of Jak/Stat or Bcl-2 (Yuan et al...Idasanutlin and combination therapy samples clustered closely in PCA analysis, with p53 response a strongly-induced pathway, as expected. Our data suggest that the rational combination of idasanutlin and navitoclax is highly active against T-ALL, with greater synergic opportunity compared to other available idasanutlin combination treatments, through induction of a p53-dependent apoptotic cell death."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • Thrombocytopenia • BCL2 • BCL2L1 • BCL2L2 • CDKN2A • MYC

Aberrant Stemness Transcription Signature Unveils a Mechanism of Chemotherapy Resistance through Blunting p53-Mediated Response in Acute Myeloid Leukemia (ASH 2024) - "Deletion of Gata2 in Gata2 high cells increased activation of p53-mediated apoptosis in response to nutlin-3...We evaluated whether MDM2 inhibitors, such as Idasanutlin, in combination with doxorubicin, could overcome the drug resistance seen in Gata2high leukemias...Our study supports a model where the "volume control" of p53-mediated apoptosis by a stem cell transcription factor is an integral part of stemness, which is imparted on leukemic cells arising from a stem-cell-like cell-of-origin. Our findings provide a mechanistic explanation for the well-established, but thus far unexplained observation that the expression of HSC signatures are associated with poor outcomes in AML."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Pediatrics • GATA2 • KMT2A • MECOM • MLLT3

High Throughput Microfluidics Platform to Assess Synthetic Lethality and Novel Therapeutic Drug Combinations (ASH 2023) - "In the context of acute myeloid leukemia (AML) specifically, several efficacious combination therapies have been approved for specific patient subsets, such as all-trans retinoic acid (ATRA) plus arsenic trioxide in the PML-RARA fusion acute promyelocytic subtype and Midostaurin plus Cytarabine and Daunorubicin in FLT3-mutant AML. Strong established hits in our screen include ATR inhibition plus Gemcitabine treatment as well as several combinations involving the BCL-2 inhibitor Venetoclax with chemotherapies (Decitabine and Daunorubicin), Quizartinib, Idasanutlin, and mTOR inhibitors. Thus, we have developed an efficient and cost-effective high throughput drug combinations profiling system that has uncovered candidate therapies that may expand treatment options for patients afflicted by AML."

IO biomarker • Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • PML

Cebpβ/IL1/TNFα Positive Feedback Loop Drives Drug Resistance of BCL2 and MDM2 Inhibitors in Monocytic Leukemia Cells (ASH 2023) - "In summary, we have described a positive feedback loop between CEBPB, IL-1/TNFα, and monocytic differentiation in monocytic leukemia that contributes to intrinsic and extrinsic drug resistance against BCL2 and MDM2 inhibitors. This crosstalk and the consequent drug resistance are further reinforced by venetoclax/MDM2 inhibition treatment. Combining venetoclax or idasanutlin with IL-1/TNFα antagonists or an IRAK inhibitor can abrogate the feedback loop and induce synergistic cytotoxic effects, offering promising therapeutic strategies to enhance the treatment efficacy of venetoclax and MDM2 inhibitors for monocytic leukemia."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BBC3 • BCL2 • BCL2A1 • CASP3 • CASP6 • CDKN1A • CEBPB • IL1B • IL1R1 • IRAK1 • IRF8 • JUNB • KLF4 • MAFB • MCL1 • PMAIP1 • SPI1 • TNFA

TRIP13 Is a Fetal-Enriched Therapeutic Target in NUP98-JARID1A+ Pediatric Non-Down Syndrome AMKL (ASH 2023) - "To exploit our mechanistic knowledge on TRIP13 ablation-mediated P53 activation, we further combined DCZ0415 with the MDM2 inhibitor Idasanutlin. In line with our mechanistic data, a high synergy (Bliss synergy score = 9.7) of TRIP13 and MDM2 inhibition was observed. In conclusion, our study uncovers TRIP13 as a fetal-enriched vulnerability in NJ-driven non-DS-AMKL, mechanistically acting through P53, which we leveraged for a mechanism-driven treatment approach with dual TRIP13/MDM2 inhibition as a potential therapeutic strategy for the treatment of high-risk pediatric non-DS-AMKL."

Clinical • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ARID1A • KDM5A • KIT • NUP98 • TRIP13

Preclinical Characterization of the Anti-Leukemia Activity of the CD123 Antibody-Drug Conjugate, Pivekimab Sunirine (IMGN632) (ASH 2024) - "Since the above data suggested that TP53 alterations impaired the ability of PVEK to induce cytotoxicity in acute myeloid and lymphoblastic leukemia cells, we used TP53wild-type EOL-1, MOLM-13, MV4; 11, REH, and RS4; 11 cells and deleted TP53 from bulk cells via CRISPR/Cas9 and then exposed these engineered cells to idasanutlin to enrich for the population of TP53KO cells. Important modulators for the drug's cytotoxic effects we identified include CD123 expression levels, TP53 alterations, and overexpression of anti-apoptotic BCL-2 family proteins but surprisingly not activity of ATP transporter proteins. The clinical relevance of these findings should be explored."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • CD123 • IL3RA

Durable Clinical Benefits of Idasanutlin Therapy in Hydroxyurea-Refractory Polycythemia Vera (ASH 2023) - P1, P2 | "HDM2 antagonist therapy represents a rational and highly effective treatment approach in PV. The durable effects of idasanutlin on phlebotomy requirements and splenomegaly persist even after treatment discontinuation. Additionally, the lack of appearance of TP53 mutations or loss of TP53 in those who progress suggest that the previously-described transient TP53 mutations do not have long-term clinical implications."

Clinical • Hematological Disorders • Myelofibrosis • Polycythemia Vera • ASXL1 • DNMT3A • JAK2 • SF3B1 • TET2 • TP53

Modeling spinal dissemination in glioblastoma using post-mortem and ex vivo approaches (EANO 2025) - "Using these cells, we successfully established a disseminating glioblastoma model in a mouse and, importantly, detected metastasis, highlighting a persistent aggressive phenotype.Carfizomib, Lurbinectedin, Panobinostat, Ixazomib, Idasanutlin, Cobimetinib and Trametinib all showed good cytotoxic activity ex- vivo. Our study highlights that the molecular pathology of spinal LM cells closely mirrors the primary tumor, and the dissemination might occur with some degree of genetic evolution. Novel treatment approaches for this aggressive tumor cell phenotype could include a personalized treatment based on the drug-screening platform results."

Preclinical • Brain Cancer • Glioblastoma • Hematological Malignancies • Oncology • Solid Tumor • MGMT • PTCH1 • TP53

PTEN and Senescence: A Critical Axis in the Pathogenesis of Ventilator-Induced Pulmonary Fibrosis (ASA 2025) - "RG7388 was administered in vivo to block MDM2-p53 interaction in PTEN knockout mice to evaluate whether PTEN regulates pulmonary fibrosis via lung EC senescence... Our study demonstrates that PTEN plays a pivotal role in MV-PF, by mediating pulmonary EC senescence. Future studies may focus on developing strategies to modulate PTEN activity and cell senescence to prevent or treat this devastating disease."

Acute Respiratory Distress Syndrome • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CDH1 • PTEN • VIM

DNA-hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation. (PubMed, J Pathol) - "Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway."

Journal • Epstein-Barr Virus Infections • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • MDM2 • MLH1 • MSI

Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial. (PubMed, Nat Med) - P1/2 | "Stratification for treatment was conducted by a trial-specific molecular tumor board across five subtrials, each evaluating a targeted therapy-alectinib, idasanutlin, palbociclib, vismodegib or temsirolimus-selected according to the best-matching molecular alteration. Patients without matching alterations were randomized between subtrials without strong biomarkers using atezolizumab and asunercept, and the standard of care (SOC), temozolomide...The results of the N2M2 trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling. ClinicalTrials.gov registration: NCT03158389 ."

Journal • P1/2 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Evaluating the Therapeutic Efficacy and Safety of Venetoclax-Based Combination Regimens in Relapsed or Refractory Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis (SOHO 2025) - "Venetoclax-based combinations included various agents such as hypomethylating agents (azacitidine), IDH inhibitors, and investigational drugs like idasanutlin (MDM2 antagonist) and mivebresib (small-molecule pan-BET inhibitor). Venetoclax-based combination regimens demonstrate encouraging efficacy in R/R AML, particularly when combined with azacitidine. However, significant myelosuppressive toxicity highlights the need for careful monitoring."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MDM2 and DNMT1 inhibitors induce neuroblastoma cell death through p53-dependent and independent pathways. (PubMed, Epigenomics) - "Importantly, DNMT1 inhibition could provide a therapeutic alternative for neuroblastomas with p53 mutations, where p53 dependent mechanism is ineffective. Our results suggest that, if validated further, RG-7388, CM-272, and SGI-1027 could become effective therapeutic agents for treating aggressive neuroblastoma that may become resistant to first or second line of treatment."

Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • BAX • BCL2L1 • CASP3 • CASP7 • CDKN1A • TP53

Synergistic MDM2-STAT3 Inhibition Demonstrates Strong Anti-Leukemic Efficacy in Acute Lymphoblastic Leukemia. (PubMed, Int J Mol Sci) - "In this study, human ALL cell lines-characterized by either wild-type or mutant tumor protein p53 (TP53) status-were treated with RG7388 (an MDM2 (mouse double minute 2 homolog) inhibitor) and BBI608 (a STAT3 (signal transducer and activator of transcription 3) inhibitor), both as single agents and in combination. This combinatorial approach augments apoptosis and tumor growth suppression, offering a promising avenue for expanding treatment options for a broader patient population. Further investigation is warranted to validate these preclinical findings and to explore translational implications in genetically diverse ALL subsets."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells. (PubMed, Mol Ther Oncol) - "DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. idasanutlin (a phase 3 clinical candidate MDM2-p53 small-molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting both MDM2 homo- and heterodimerization in TP53 wild-type and mutant cancers with an MDM2-derived disruptor peptide."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • TP53