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 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

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