idasanutlin (RG7388) / Roche - LARVOL DELTA

Delivery of ATSP-7041 by Minimally Invasive Nasal Depot (MIND) to Target Diffuse Intrinsic Pontine Glioma. (PubMed, Mol Cancer Ther) - "In p53-wild-type, PPM1D-mutant DIPG neurospheres (BT869), ATSP-7041 exhibited ∼125-fold greater antitumor activity than the HDM2-selective antagonist RG7388, consistent with elevated HDMX expression. This feasibility study provides proof of concept for on-target p53 reactivation in DIPG using a BBB-penetrant dual HDM2/HDMX inhibitor delivered by the MIND platform. The findings support a translational path for ALRN-6924, the clinical analogue of ATSP-7041, in DIPG and potentially other brain tumors that retain wild-type p53 but remain incurable because of drug resistance and restricted CNS access."

Journal • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • PPM1D

Comparative in vivo evaluation of RG-7388, CM-272, and SGI-1027 to determine epigenetic targeting as an effective strategy for treating high-risk neuroblastoma (AACR 2026) - "Epigenetic targeting of DNMT and G9a using CM-272 produced the strongest anti-tumor and survival benefit in the SK-N-AS CDX model, outperforming both RG-7388 and SGI-1027. CM-272's ability to simultaneously inhibit DNMT1 and G9a, appears to reduce repressive chromatin marks, and activate apoptosis cascade that highlights its translational potential for treating TP53-mutant and epigenetically driven neuroblastoma. These initial findings suggest advancing preclinical optimization and combination-therapy strategies involving CM-272 for high-risk neuroblastoma."

Preclinical • Neuroblastoma • Oncology • Solid Tumor • DNMT1

Extrachromosomal MDM2 amplifications define an ecDNA-permissive tumor cell state that impacts intercellular tumor heterogeneity and treatment response across cancers (AACR 2026) - "Whereas chemotherapy rapidly enriched for ecDNA-high cells with reduced TP53 signaling, pharmacologic MDM2 inhibition (Nutlin-3a/Idasanutlin) selectively eliminated ecDNA-high subclones through TP53-dependent apoptosis...Our study demonstrates that MDM2 ecDNA is the predominant ecDNA oncogene in human cancers and defines an ecDNA-permissive state in TP53-wildtype tumors which facilitates rapid adaptation to different therapeutic pressures. These results identify MDM2 ecDNA copy number variation as a functional determinant of acute treatment responses and reveal MDM2-regulated TP53 function as a vulnerability in ecDNA-carrying cancers that may be exploited through rational treatment sequencing."

Heterogeneity • Tumor cell • Astrocytoma • Brain Cancer • Neuroblastoma • Oncology • Solid Tumor • MDM2 • MYCN

APOBEC4, a novel regulator of p53-dependent tumor suppression (AACR 2026) - "Our findings identify APOBEC4 as a novel regulator of p53-dependent cell cycle arrest, senescence, apoptosis, and tumor suppression, highlighting its potential as a biomarker for p53-targeted therapies."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CDKN1A • GADD45A

Combination of MDM2 inhibitor and lipophilic gemcitabine: Strong synergism in lung cancer, while antagonism in brain cancer (AACR 2026) - "Combination therapy is therefore recognized as a powerful strategy to enhance therapeutic efficacy and delay resistance.In this study, we investigated the synergistic potential of Idasanutlin (Ida), a second-generation MDM2 inhibitor, and Gemcitabine Elaidate (Gem Eli), a lipophilic prodrug of Gemcitabine, for the treatment of non-small cell lung cancer (NSCLC) and glioblastoma (GBM)...Cryo-electron microscopy confirmed uniform particle morphology with no evidence of aggregation. Ongoing studies are focused on elucidating the cellular mechanisms underlying the observed antagonism in GBM."

Brain Cancer • Glioblastoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Deciphering radiation sensitivity identifies MDM2 as a targetable driver of synergistic radiosensitization in TP53 wild-type lung adenocarcinoma (AACR 2026) - "Our findings demonstrate that MDM2 dependency, revealed through integrative omics analyses, represents a therapeutic vulnerability underlying IR-resistance in p53-proficient LUAD. Combining idasanutlin with radiotherapy effectively overcomes this resistance, highlighting MDM2 as a robust and actionable target for enhancing radiation response in cancers driven by high MDM2 activity."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Epigenetic modulation by MDM2 and DNMT inhibitor promotes cell cycle arrest and programmed cell death in neuroblastoma cells (AACR 2026) - "To assess the effects of RG-7388, CM-272,and SGI-1027, the neuroblastoma cells were treated for 24 hrs, then qRT-PCR analyses wereconducted to evaluate the gene expressionlevels of DNMT-1, DNMT-3A, DNMT-3B, G9a,EZH2, TET-2, TET-3, MDM2, p53, p21, and PARP...So far, our findingsindicatethatRG-7388, CM-272, and SGI-1027 treatments effectivelydownregulate the expressionofDNMTs, whileupregulatingp21 levels inIMR-32 cells, leadingto cell cycle arrest andapoptosis.The abilityof these experimentalcompounds to inducecell cycle arrest and cell deathsuggests that further evaluationof these compounds could lead to the identificationof apromisingtherapeuticagent for treatingaggressiveneuroblastoma.(Thisprojectwas supported by the NationalPediatricCancer Foundation(NPCF) and The RoyalDames of Cancer Research Inc., Ft. Lauderdale, Florida)"

Neuroblastoma • Oncology • Solid Tumor • BAX • CDKN1A • DNMT1 • DNMT3A • EZH2

Delivery of ATSP-7041 by Minimally Invasive Nasal Depot (MIND) to Target Diffuse Intrinsic Pontine Glioma. (PubMed, Mol Cancer Ther) - "In p53-wild-type, PPM1D-mutant DIPG neurospheres (BT869), ATSP-7041 exhibited ~125-fold greater anti-tumor activity than the HDM2-selective antagonist RG7388, consistent with elevated HDMX expression. This feasibility study provides proof-of-concept for on-target p53 reactivation in DIPG using a BBB-penetrant dual HDM2/HDMX inhibitor delivered by the MIND platform. The findings support a translational path for ALRN-6924, the clinical analog of ATSP-7041, in DIPG and potentially other brain tumors that retain wild-type p53 but remain incurable due to drug resistance and restricted CNS access."

Journal • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • PPM1D

Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial. (PubMed, Blood Adv) - P3 | "Adults (N=447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 intravenously on days 1 to 5 of 28-day cycles. Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML."

Journal • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • MDM2 • TP53

N2M2/NOA-20: Phase I/IIa umbrella trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. (ASCO 2024) - P1/2 | "Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ)...The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug... N 2 M 2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients."

Clinical • P1/2 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CDK4 • CDKN2A • CDKN2B

Venetoclax and idasanutlin in relapsed/refractory AML: a non-randomized, open-label phase 1b trial. (PubMed, Blood) - P1 | "IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were pre-existing. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations."

IO biomarker • Journal • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • BCL2 • IDH1 • IDH2 • RUNX1 • TP53

Oxymatrine Alleviates Atherosclerosis by Regulating Macrophage Senescence via the SIRT1-P53 Signaling Pathway. (PubMed, Phytother Res) - "Functional validation assays revealed that the effects of OMT were aborted by EX527 and SIRT1 shRNA...Furthermore, Idasanutlin attenuated the functional effects of OMT, which indicated the pivotal role of P53...Consequently, this process delays macrophage senescence-induced foam cell formation, ultimately ameliorating AS. Our findings suggest OMT as a promising therapeutic candidate for AS."

Journal • Atherosclerosis • Cardiovascular • Targeted Protein Degradation • APOE • SIRT1

MDM2 amplification enables selective PROTAC targeting of tumor cells. (PubMed, Mol Cancer Ther) - "To investigate whether MDM2 can serve as tumor-specific PROTAC E3 in certain setting, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. Importantly, A1874 showed on average ~12-fold higher potency in tumor cells with MDM2 amplification compared to non-amplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using PROTAC approach."

Journal • Oncology • Targeted Protein Degradation • BRD4 • CRBN • MDM2

DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia. (PubMed, Cancers (Basel)) - "These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO."

Journal • Hematological Malignancies • Leukemia • Oncology • TP53

Discovery of Histone Deacetylase 8-Specific Proteolysis-Targeting Chimeras with Anticancer Activity against Hematological Malignancies. (PubMed, J Med Chem) - "The pomalidomide/thalidomide-based series (BP1-BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • HDAC8 • TP53

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