Treatment Of Acute Myeloid Leukemia Research Articles

Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia.

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure-activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 μM) and MOLM-13 (IC50 = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.

Anti-Tumor Activity of Indole: A Review

: Generally, heterocyclic compounds are included in a large class of pharmacologically active compounds. The indole scaffold in this category is widely distributed in nature and present in many active compounds, especially anti-cancer agents. Due to its unique physicochemical and biological properties, the indole platform has been considered a favorable scaffold in anti-cancer drug design and development. Various indole compounds (synthetic, semisynthetic, and natural) show remarkable anti-proliferative activity. According to the recent literature, this review describes the role of indole scaffolds as anti-cancer agents. Indole was reported to induce anti-tumor activity through multiple mechanisms, for example, Epidermal Growth Factor Receptors (EGFR), histone deacetylase (HDAC), kinase, DNA-topoisomerases, and tubulin inhibition. The current review focuses on some indole compounds with amazing effects against different types of cancers as there are too many FDA-approved drugs, for example, osimertinib, alectinib, and anlotinib in NSCLC treatment, panobinostat in multiple myeloma, midostaurin in acute myeloid leukemia treatment, etc. Moreover, several compounds are still in clinical trials to treat different cancer types. Additionally, there are some oxindole derivatives with potent inhibition against different types of tumors, such as ovarian cancer, colorectal cancer, and prostate cancer. Different series of oxindoles are promising and recommended for further studies due to their remarkable inhibition of tumor cells. Accordingly, the collection of data on a pharmacologically significant motif might aid researchers in further employing indoles in developing novel anti-cancer drugs with potentially fewer side effects and higher potency against this rapidly spreading disease.

Specific surface-modified iron oxide nanoparticles trigger complement-dependent innate and adaptive antileukaemia immunity

Considerable advances have been achieved in the application of nanomaterials for immunotherapies, yet the precise immune effects induced by protein corona remain elusive. Here, we explore the formation mechanism and immune regulation process of protein corona in acute myeloid leukaemia (AML) mouse models using commercialized iron oxide nanoparticles (IONPs), with different surface modifications, including an FDA-approved variant. Using macrophages depleted or Complement Component 3 (C3) knockout mice, we demonstrate that carboxymethyl dextran-coated IONP (IONP-COOH) reduces leukaemia burden. Mechanistically, IONP-COOH indirectly binds to C3b after activating the complement alternative pathway, subsequently enhancing phagocytosis of macrophages and activating adaptive immunity mediated by complement corona. While aminated dextran-coated IONPs directly absorb C3b and activate the lectin pathway, leading to immune cell exhaustion. Our findings suggest that IONP-COOH may serve as an immune activator for AML treatment, offering a promising approach to developing therapeutic nanomaterials by leveraging surface chemistry to enhance immunotherapy.

Targeting chromatin modifying complexes in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy with high rates of relapse, which can, in part, be attributed to the dysregulation of chromatin modifications. These epigenetic modifications can affect the capacity of hematopoietic cells to self-renew or differentiate, which can lead to transformation. Aberrant histone modifications contribute to the derepression of self-renewal genes such as HOXA/B and MEIS1 in committed hematopoietic progenitors, which is considered a key mechanism of leukemogenesis in MLL-rearranged (MLL-r) and NPM1-mutated AML. As regulators of some of the key histone modifications in this disease, the menin-KMT2A and polycomb repressive (PRC1/2) complexes have been identified as promising targets for the treatment of AML. This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.

Identification of inhibitors targeting the FLT3-ITD mutation through 4D-QSAR, in vitro, and in silico

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation is a key target for acute myeloid leukemia (AML) treatment. The second-generation inhibitors such as Gilteritinib still present off-target effects and associated side effects. Therefore, identifying novel FLT3-ITD inhibitors has become a promising strategy for AML treatment. In this study, a 4D-QSAR model was developed based on Gilteritinib and its analogues, and it was found that introducing hydrophobic bulky groups at the piperazine or piperidine of Gilteritinib would enhance the binding affinity to FLT3-ITD. So, three series of targeted compounds (A1-A5, B1–B5 and C1–C5) were designed and synthesized. The antiproliferative activity against MOLM-13 cells was evaluated in vitro. Compound A1 (IC50 = 25.65 nM), with a cubane group at the piperazine position; Compounds B2 (IC50 = 63.38 nM) and C2 (IC50 = 54.96 nM), with a norbornene group at the piperidine position, showed the strongest inhibition in their series. Their IC50 values were comparable to that of the positive control Gilteritinib (IC50 = 22.37 nM). FLT3-ITD was confirmed as the degradation target through a kinase inhibition assay, where the IC50 values were 2.12 nM (Compound A1), 1.29 nM (Compound B2), and 3.06 nM (Compound C2), which were comparable to that of Gilteritinib (IC50 = 0.43 nM). Additionally, molecular docking and molecular dynamics (MD) simulations showed that Compounds A1, B2, and C2 had similar binding modes to that of Gilteritinib with more stable affinities. Overall, these results demonstrated that Compounds A1, B2, and C2 were promising inhibitors for targeting AML with FLT3-ITD mutation.

The time factor and the allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

Introduction. The current overall effectiveness of acute myeloid leukemia (AML) treatment is largely ensured by the integration of transplantation technologies, but not all patients who are indicated to undergo transplantation of allogeneic hematopoietic stem cells (allo-HSCT) can reach this stage.Aim: to analyze the time and volume of the implementation of allo-HSCT in patients with AML in the first complete remission (1CR).Materials and methods. Between January 2020 and December 2023, 477 AML patients from 43 different regions of the Russian Federation were referred to the NMRC for Hematology for the possibility of performing allo-HSCT. In this cohort of patients, the following time parameters were analyzed: days from diagnosis of AML to primary treatment at the transplant center, from primary treatment to search for a donor (related or non-related), from diagnosis of AML to allo-HSCT, from the achievement of 1CR to allo-HSCT.Results. 175 (36.7 %) patients, agreed upon by the Transplant Commission, were selected to undergo allo-HSCT. Of these, only 163 patients, who had allo-HSCT performed before January 2024, were included in further analysis. It was not possible to implement allo-HSCT in the other 236 agreed upon cases due to the following reasons: refusal of the patient — 110 (46.6 %), relapse — 48 (20.3 %) patients, death — 23 (9.7 %) patients. Median time from 1CR to allo-HSCT was 6.8 (0.3– 26) months for all patients: for a related fully compatible donor 5.8 (0.5–26.0) months, for a haploid donor — 6.1 (0.3–23.5) months, in case of non-related — 8.0 (0.6–8.6) months. In 5 years, the NMRC for Hematology managed to reduce the time to the general allo-HSCT in 1CR for patients with AML from 6.5 months in 2018 to 5.8 months in 2023. Also, under the current “AML-21” protocol, the time from 1CR to allo-HSCT in patients included in the multicenter study was minimized to — 4.8 (0.33–11.0) months, and for AML patients from the poor prognosis group — 3.4 (0.33–8.0 months).Conclusion. In addition to achieving full, optimally — MDR-negative remission, the absence of severe concomitant pathology, and the presence of a donor, the time factor must also be considered. In order to cure more AML patients, it is necessary to bring the implementation of allo-HSCT to the earliest possible date after achieving 1CR.

Preclinical activity of resazurin in acute myeloid leukaemia.

Resazurin, a phenoxazine used in cell viability assays, acts invitro as an anti-leukaemic compound through the production of cellular reactive oxygen species (ROS) resulting in mitochondrial dysfunction and cell death. However, the invivo tolerance and efficacy of resazurin in cancer are unknown. In this study, we investigated the invitro and invivo effects of resazurin in acute myeloid leukaemia (AML). Resazurininduced cell death in a dose-dependent manner in AML cell lines and reduced proliferation and colony formation in exvivo treated patient-derived AML cells. Cells treated with a reduced dose of resazurin for 72 h acquired a more mature immunophenotype suggesting cell differentiation as a mechanism contributing to the anti-leukaemic effect. Invivo optical imaging in healthy mice demonstrated a reduction of resazurin to resorufin within 30 min and non-detectable after 2 h, supporting dosing twice daily as optimal. In subcutaneous and orthotopic models of MV4-11 AML in NOD/SCID IL2rγnull mice, anti-tumour effects and an increased survival were found at a dose level of 75 mg/kg twice daily without observed toxicity. Our results suggest that resazurin represents a novel experimental therapeutic for the treatment of AML.

Bilosomes and Niosomes for Enhanced Intestinal Absorption and In Vivo Efficacy of Cytarabine in Treatment of Acute Myeloid Leukemia

Cytarabine (CTR) is a hydrophilic anticancer drug used to treat leukemia. It suffers from poor permeability and intestinal metabolism, diminishing its oral bioavailability. Background/Objectives: The objective was to develop and evaluate niosomes and bilosomes for enhanced intestinal absorption; hence, oral bioavailability. Results: CTR-loaded niosomes and bilosomes with vesicle sizes of 152 and 204.3 nm were successfully prepared with acceptable properties. The presence of bile salts increased the zeta potential of bilosomes. The recorded entrapment efficiency of cytarabine was acceptable for such a hydrophilic drug. CTR-bilosomes showed a pH-dependent drug release pattern with preferred release in pH 6.8. Intestinal absorption behavior indicated a site-dependent CTR absorption pattern with unfavorable absorption in the distal intestine. Niosomal and bilosomal formulations enhanced intestinal absorption parameters with evidence for a predominant paracellular absorption mechanism that bypasses intestinal barriers. The investigation of the anti-leukemic effect of niosomal and bilosomal formulations indicated that both formulations ameliorated the blood parameters, reflecting significant improvement in leukemia treatment compared with the drug solution. Pathological examination of blood films revealed decreased blast cells in peripheral blood in groups treated with tested formulations. Methods: Tested formulations were prepared according to the pro-concentrate method and characterized for particle size, zeta potential, entrapment efficiency, and in vitro release. CTR-loaded niosomes and bilosomes were evaluated for enhanced intestinal absorption utilizing the single-pass in situ intestinal perfusion method in rabbits, and the anti-leukemic effect was assessed using the benzene-induced leukemia model in rats. Conclusions: This study introduced surfactant vesicles for enhanced oral bioavailability of CTR.

METTL3/YTDHF1 Stabilizes CSRP1 mRNA to Regulate Glycolysis and Promote Acute Myeloid Leukemia Progression.

CSRP1 (Cysteine and Glycine-Rich Protein 1) is a protein often overactivated in various cancers, promoting cell proliferation and survival, making it a key factor in cancer development. However, it is worth noting that the effect of this protein on the glycolysis process in Acute Myeloid Leukemia (AML) has not yet been studied. This study aims to investigate the role of the METTL3/YTHDF1 axis in regulating Glycolysis and its impact on AML progression by stabilizing CSRP1 mRNA. We analyzed CSRP1 expression in AML tissues and cell lines using quantitative real-time PCR (qRT-PCR) and Western blotting. Functional assays, including cell viability, colony formation, glycolysis related indicators, were performed to assess the impact of CSRP1 knockdown or overexpression on AML cells. RNA immunoprecipitation (RIP) and RNA stability assays were conducted to elucidate the mechanism of METTL3/YTHDF1-mediated regulation of CSRP1 mRNA. CSRP1 was significantly upregulated in AML tissues and cell lines. Knockdown of CSRP1 inhibited AML cell proliferation and glycolysis. Overexpression of CSRP1 promoted AML cell survival. Mechanistically, METTL3 enhanced CSRP1 mRNA stability via m6A modification, recognized and bound by YTHDF1, preventing mRNA degradation. The METTL3/YTHDF1/ CSRP1 axis plays a critical role in AML progression by regulating glycolysis. Targeting this pathway may provide a novel therapeutic strategy for AML treatment.

Unveiling the Role of New Molecules in Acute Myeloid Leukemia: Insights into Disease Pathogenesis and Therapeutic Potential

This review article explores the current landscape of acute myeloid leukemia treatment, including novel target molecules and recent advancements in cell therapy and immunotherapy focused on T cell activity. Advances in treatment have been promising in recent years, driven by the development of therapies targeting new molecular and genetic therapeutic targets. These findings allowed for the approval of several target therapies by the European and American drug agencies in the last 5 years. However, mortality remains very high, particularly in relapsed or refractory (R/R) patients. In recent years, the development of immunotherapy has expanded this field, leading to the introduction of new drugs and treatments.

Identification and validation of a novel prognostic model based on anoikis‑related genes in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological cancer prevalent worldwide. Anoikis-related genes (ARGs) are crucial in the progression of cancer and metastasis of tumors. However, their role in AML needs to be clarified. In the present study, differential analysis was performed on data from The Cancer Genome Atlas database to identify differentially expressed ARGs (DE-ARGs). Subsequently, a prognostic model for patients with AML was constructed using univariate Cox, Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses. This model was based on four key DE-ARGs [lectin galactoside-binding soluble 1 (LGALS1), integrin subunit α 4 (ITGA4), hepatocyte growth factor (HGF) and Ras homolog gene family member C (RHOC)]. Independent prognostic factors for AML included prior treatment, age, risk scores and diagnosis. A nomogram was constructed based on these factors to aid clinical decision-making. Furthermore, bone marrow samples were collected from individuals diagnosed with AML and healthy donors to validate the expression of the identified ARGs using reverse transcription-quantitative PCR. The mRNA levels of LGALS1 and RHOC were significantly higher, while those of ITGA4 and HGF were significantly lower in patients with AML than in healthy donors (all P<0.05). The results of the present study expands the understanding of the function of ARGs in AML, providing a new theoretical basis for the treatment of AML.

Longitudinal ultra-sensitive mutation burden sequencing for precise minimal residual disease assessment in AML

Relapse is one of the major challenges in clinical treatment of acute myeloid leukemia (AML). Though minimal residual disease (MRD) monitoring plays a crucial role in quantitative assessment of the disease, molecular MRD analysis has been mainly limited to patients diagnosed with gene fusions and NPM1 mutations. Here, we report a longitudinal ultra-sensitive mutation burden (UMB) monitoring strategy for accurate MRD analysis in AML patients regardless of genetic abnormality types. Using a Quantitative Blocker Displacement Amplification (QBDA) sequencing panel with limit of detection below 0.01% variant allele frequency (VAF), a hazard ratio of 14.8 (p < 0.001) is observed in cumulative incidence of relapse analysis of 20 patients with ≥ 2 samples during complete remission (CR). The ROC area under curve (AUC) is 0.98 when predicting relapse within 30 weeks of CR timepoint 2 (N = 20). Furthermore, we demonstrate quantitating VAF below 0.01% is essential for accurate relapse prediction.

Loop33 × 123 CAR-T targeting CD33 and CD123 against immune escape in acute myeloid leukemia

BackgroundImmunotherapy, such as chimeric antigen receptor T (CAR-T) cells targeting CD33 or CD123, has been well developed over the past decade for the treatment of acute myeloid leukemia (AML). However, the inability to sustain tumor-free survival and the possibility of relapse due to antigen loss have raised concerns. A dual targeting of CD33 and CD123 is needed for better outcomes.MethodsBased on our previously constructed CD33 and CD123 monovalent CAR-T, Loop33 × 123 and Loop123 × 33 CAR-T were constructed with molecular cloning techniques. All CAR-T cells were generated by lentivirus transduction of T cells from healthy donors. Phenotype detection was evaluated on day 7 concerning activation, exhaustion, and subtype proportions. Coculture killing assays were conducted using various AML cell lines and primary AML cells. Degranulation and cytokine secretion levels were detected by flow cytometry. Cell-derived xenograft models were established using wild-type Molm 13 cell lines, or a mixture of Molm 13-KO33 and Molm 13-KO123 cells as an ideal model of immune escape. By monitoring body weight and survival of tumor-bearing mice, Loop33 × 123 and Loop123 × 33 CAR-T cells were further assessed for their efficacy in vivo.ResultsIn vitro study, our results demonstrated that Loop33 × 123 CAR-T cells could efficiently eliminate AML cell lines and primary AML cells with elevated degranulation and cytokine secretion levels. Compared with our previously constructed monovalent CD33 or CD123 CAR-T cells, Loop33 × 123 CAR-T cells showed superior advantages in an immune escape model. In vivo studies further confirmed that Loop33 × 123 CAR-T cells could effectively prolong the survival of mice without significant toxicity. However, Loop123 × 33 CAR-T cells failed to show the same effects. Furthermore, Loop33 × 123 CAR-T cells efficiently circumvented potential immune escape, a challenge where monovalent CAR-T cells failed.ConclusionsLoop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape.

NAP1L5 promotes epithelial–mesenchymal transition by regulating PEG10 expression in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a haematological malignancy that poses a serious threat to human health. Studies have shown that the expression of NAP1L5 is elevated in patients with AML; however, the specific molecular mechanism remains unknown. Therefore, in this study, we aimed to investigate the pathogenic mechanisms of NAP1L5 in AML. The expression level of NAP1L5 was increased in AML, and the upregulation of NAP1L5 was related to tumour growth and epithelial–mesenchymal transition. Furthermore, PEG10 is a downstream regulatory factor of NAP1L5, and its overexpression promotes tumour growth and epithelial–mesenchymal transition. More importantly, the loss of PEG10 inhibited the negative effects induced by NAP1L5 overexpression. Our results suggest that NAP1L5 is a novel therapeutic target for AML treatment.

Targeting the Tumour Antigen 5T4 using CAR-T Cells for the Treatment of Acute Myeloid Leukaemia.

Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and eradicate tumours. 5T4 is a tumour-associated antigen expressed on the cell surface of most solid tumours. However, very little is known about its expression in haematological malignancies. Herein, we assess the expression of 5T4 in different types of leukaemias, specifically Acute Myeloid Leukaemia (AML), and normal haematopoietic stem cells (HSCs). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR-T cells against HSCs and AML tumour cell lines. 5T4 expression was seen in about 50% of AML cases, specifically AML with mutated NPM1, AML-MR and NOS. 5T4 CAR-T cells efficiently and specifically killed AML tumour cell lines, including the Leukaemic Stem Cells. Co-culture of 5T4 CAR-T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A murine model for AML demonstrated that CAR-T cells recognise and kill in vivo 5T4-expressing tumour cells. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR-T cells can be considered a powerful personalised therapeutic approach to treat AML.

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50(MOLM-13): 1.25 ± 0.18 μM; CC50(MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML.

The treatment of acute myeloid leukemia (AML) presents a challenge to current therapies because of the development of drug resistance. Genetic mutation of FMS-like tyrosine kinase-3 (FLT3) is a target of interest for AML treatment, but the use of FLT3-targeting agents on AML patients has so far resulted in poor overall clinical outcomes.[1] The incorporation of the boronic group in a drug scaffold could enhance the bioavailability and pharmacokinetic profile of conventional anticancer chemotypes. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML, and they are only scantly reported as inhibitors of protein kinases. We identified α-triazolylboronic acids as a novel chemotype for targeting FLT3 by screening a library of structurally heterogeneous in-house boronic acids. Selected compounds show low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Furthermore, control analogues synthesized ad hoc and lacking the boronic acid are inactive, confirming that this group is essential for the activity of the series. All together, these results suggest α-triazolylboronic acids could be a promising novel chemotype for FLT3 inhibition, laying the ground for the design of further compounds.

Outcomes with intensive treatment for acute myeloid leukemia: an analysis of two decades of data from the HARMONY Alliance.

Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcome of patients with acute myeloid leukemia (AML). However, even before these innovations outcomes with intensive chemotherapy have improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5- year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate has dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients.

10-Year Real-World Data on Acute Myeloid Leukemia:

Introduction: Despite advances in Acute Myeloid Leukemia (AML) diagnosis and treatment, the outcomes in low- and middle-income countries (LMIC) are far apart from those in high-income countries (HIC). Objective: To describe the clinical features and outcomes of AML patients in Brazil's public health system, we conducted a retrospective analysis of all cases of non-promyelocytic AML diagnosed within 10 years (2007- 2017) in northeastern Brazil, Bahia. Methodology: We analyzed the real-life outcomes of 62 patients diagnosed with non-promyelocytic AML between 2007 and 2017 at a university hospital in Northeast Brazil. We classified patients using the European LeukemiaNet 2022 guideline into favorable (n=8), intermediate (n=18), and adverse risk (n=7) groups. Twenty-nine were not otherwise classified because no cytogenetic and/or molecular tests were available at diagnosis. Results: Allogeneic bone marrow transplant (alloBMT) was performed in 16 patients (37%). Median overall survival (mOS) was seven months. Among patients receiving alloBMT, mOS was 49 months, while for the chemotherapy group, it was six months (P = 0.003). For 10-year real-life data, we found complete remission of 53%, 5-year OS of 27%, and a mortality rate during induction therapy of 27%, inferior to HIC. Conclusion: Inferior outcomes found in LMIC result from a multifactorial scenario and an unmet need in the worldwide panorama of AML.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.