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  • ||||||||||  ziftomenib (KO-539) / Kura Oncology, Idhifa (enasidenib) / BMS, Servier, Tibsovo (ivosidenib) / Servier
    Combination of Menin and IDH Mutant Inhibition in Acute Myeloid Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_4070;    
    A close analogue of this compound, KO-539 (Ziftomenib) is now being tested in clinical trials in refractory and relapsed AML patients (NCT 04067336)...Colony formation assays with these AML patient samples were performed in methylcellulose media with cells treated with a concentration range of MI-3454, ivosidenib (IDH1 inhibitor) or enasidenib (IDH2 inhibitor) as single agents and in combinations...Overall, our study demonstrates that combination of MI-3454 and IDH mutant inhibitors outperforms the effect of single agents with respect to their anti-leukemic effects in clinically relevant pre-clinical models. These results support that combination of menin and IDH mutant inhibitors could be utilized in clinical trials to improve the ability of patients with AML to achieve remission.
  • ||||||||||  ziftomenib (KO-539) / Kura Oncology
    Preclinical In Vivo Activity of the Menin Inhibitor Ziftomenib (KO-539) in Pediatric KMT2A-Rearranged Acute Lymphoblastic Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2366;    
    Ziftomenib monotherapy activity was further augmented in most models when combined with conventional chemotherapy drugs vincristine or dexamethasone, which were well-tolerated in PDX mice. Based upon early clinical safety/tolerability data for ziftomenib in adult patients with acute leukemias and our pediatric-specific data described herein, a phase 1 clinical trial of ziftomenib in combination with multi-agent chemotherapy for children with relapsed/refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemias is planned.
  • ||||||||||  ziftomenib (KO-539) / Kura Oncology, Xospata (gilteritinib) / Astellas
    Mutational Landscape of Mixed Phenotype Acute Leukemia Reveals Targetable Mutations () -  Oct 24, 2022 - Abstract #AMP2022AMP_401;    
    In one the largest series of MPAL cases to date, we corroborate previous findings with enriched detection of RUNX1 and FLT3-ITD mutations along with discovery of unreported mutations (MAP3K) that may be amenable to therapeutic manipulation. Our findings support the need to genomically profile MPAL cases to exploit opportunities for targeted therapies in this orphan disease with dismal prognosis.
  • ||||||||||  MI-503 / Kura Oncology
    Journal:  Direct targeting of epigenetic regulator Menin inhibits neuroblastoma growth. (Pubmed Central) -  May 14, 2022   
    Inhibition of menin-MLL1 interaction by a specific small-molecule inhibitor MI-503 leads to the inhibition of epigenetic regulator functions and inhibits NB growth. Our future efforts will focus on further elucidating the role of menin in NB and to develop effective therapeutic strategies incorporating epigenetic inhibitors for NB patients.
  • ||||||||||  SNDX-5613 / Syndax Pharma, ziftomenib (KO-539) / Kura Oncology
    Review, Journal:  Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021). (Pubmed Central) -  May 6, 2022   
    In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.
  • ||||||||||  MI-503 / Kura Oncology
    Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations. (Available On Demand; 239) -  Apr 28, 2022 - Abstract #ASCO2022ASCO_3792;    
    In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology.
  • ||||||||||  ziftomenib (KO-539) / Kura Oncology
    Enrollment change, Trial completion date, Trial primary completion date:  KOMET-001: First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) -  Apr 22, 2022   
    P1/2,  N=60, Recruiting, 
    Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology. N=90 --> 60 | Trial completion date: Aug 2022 --> Dec 2022 | Trial primary completion date: Feb 2022 --> Jun 2022
  • ||||||||||  MI-2 / University of Michigan
    Journal:  IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. (Pubmed Central) -  Apr 1, 2022   
    The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480iNOS MΦs, vimentin fibroblasts, and CD3 T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.
  • ||||||||||  PP2 / University of Michigan, Pfizer
    Journal:  Sulforaphane Activates a Lysosome-dependent Transcriptional Program to Mitigate Oxidative Stress. (Pubmed Central) -  Nov 29, 2021   
    Notably, TFEB activity is required for SFN-induced protection against both acute oxidant bursts and chronic oxidative stress. Hence, by simultaneously activating macroautophagy/autophagy and detoxifying pathways, natural compound SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases.
  • ||||||||||  MI-503 / Kura Oncology
    Deciphering molecular mechanisms that control sensitivity and resistance to menin-MLL1 inhibition in NPM1 mutated AML (A5) -  Sep 20, 2021 - Abstract #DGHO2021DGHO_35;    
    By exposing AML cells to increasing concentrations of the Men-i MI503, we developed three cell clones that demonstrated profound resistance against two novel Men-is compared to parental and vehicle-treated long-term cultured cells... This study provides inside into the molecular mechanisms that control sensitivity and resistance to Men-i and will improve efforts to develop novel combinatorial treatment approaches against AML.
  • ||||||||||  pinometostat (EPZ-5676) / Epizyme, BMS, KO-539 / Kura Oncology, eprenetapopt (APR-246) / Aprea
    Review, Journal:  Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches. (Pubmed Central) -  Aug 11, 2021   
    AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
  • ||||||||||  MI-503 / Kura Oncology
    Preclinical, Journal:  Menin-MLL inhibitor blocks progression of middle ear cholesteatoma in vivo. (Pubmed Central) -  Jun 22, 2021   
    Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML. We demonstrated that inhibition of the menin-MLL interaction may be a potentially useful strategy in the conservative treatment of cholesteatoma.
  • ||||||||||  ziftomenib (KO-539) / Kura Oncology
    Phase classification, Enrollment change, Trial completion date, Trial primary completion date:  KOMET-001: First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) -  Jan 8, 2021   
    P1/2,  N=100, Recruiting, 
    Results N/A (trial in progress) Conclusion N/A (trial in progress) Phase classification: P1 --> P1/2 | N=30 --> 100 | Trial completion date: Jun 2021 --> Aug 2022 | Trial primary completion date: Jan 2021 --> Feb 2022
  • ||||||||||  KO-539 / Kura Oncology
    Journal:  AML Prognoses Better with Menin-MLL Inhibitor? (Pubmed Central) -  Jan 2, 2021   
    Phase classification: P1 --> P1/2 | N=30 --> 100 | Trial completion date: Jun 2021 --> Aug 2022 | Trial primary completion date: Jan 2021 --> Feb 2022 The investigational menin-MLL inhibitor KO-539 may be active in patients with acute myeloid leukemia: In a phase I trial, the agent induced complete remissions in two patients with relapsed/refractory disease and showed signs of activity in several others.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, MI-503 / Kura Oncology
    [VIRTUAL] DYRK1A Is Required to Alleviate Replication Stress in KMT2A-Rearranged Acute Lymphoblastic Leukemia (Channel 13 (Virtual Meeting)) -  Nov 5, 2020 - Abstract #ASH2020ASH_4489;    
    Pharmacologic inhibition of DYRK1A resulted in significant growth disadvantage of KMT2A-R ALL cells due to increased MYC and CHK1 proteins that induce replication stress. While further in vivo studies are needed, we predict that combining DYRK1A inhibition with venetoclax may be a novel precision medicine strategy for KMT2A-R ALL that is translatable to the clinic for patients with these high-risk leukemias.