Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

/pdf/lsd1-kdm1a-inhibitors-in-clinical-trials-advances-and-2go26g7jmm.pdf

LSD1/KDM1A inhibitors in clinical trials: advances and prospects.

Venetoclax-based therapies for acute myeloid leukemia.

Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.

/pdf/recent-developments-in-epigenetic-cancer-therapeutics-1xc5z4aq7c.pdf

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

Histone lysine-specific demethylase 1 (LSD1/KDM1A) has become an important and promising anticancer target since it was first identified in 2004 and specially demethylates lysine residues of histone H3K4me1/2 and H3K9me1/2. LSD1 is ubiquitously overexpressed in diverse cancers, and abrogation of LSD1 results in inhibition of proliferation, invasion, and migration in cancer cells. Over the past decade, a number of biologically active small-molecule LSD1 inhibitors have been developed. To date, six trans-2-phenylcyclopropylamine (TCP)-based LSD1 inhibitors (including TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, and ORY-2001) that covalently bind to the flavin adenine dinucleotide (FAD) within the LSD1 catalytic cavity have already entered into clinical trials. Here, we provide an overview about the structures, activities, and structure-activity relationship (SAR) of TCP-based LSD1 inhibitors that mainly covers the literature from 2008 to date. The opportunities, challenges, and future research directions in this emerging and promising field are also discussed.

Tranylcypromine Based Lysine-Specific Demethylase 1 Inhibitor: Summary and Perspective.

Richter transformation (RT), defined as the development of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), represents a clinical unmet need because of its dismal prognosis. An increasing body of knowledge in the field of RT is arising from the recent development of preclinical models depicting the biology underlying this aggressive disease. Consistently, new therapeutic strategies based on a genetic rationale are exploring actionable pathogenic pathways to improve the outcome of patients in this setting. In this review, we summarize the current understandings on RT biology and the available treatment options.

/pdf/biology-and-treatment-of-richter-transformation-1ihah2qw.pdf

Biology and Treatment of Richter Transformation

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

/pdf/bet-proteolysis-targeted-chimera-based-therapy-of-novel-3o89eaxes0.pdf

BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Synergistic Pre-Clinical Activity of Targeted Inhibition of KDM1A and BET Proteins Against Human AML Blast Progenitor Cells

Mechanisms Underlying Superior Efficacy of Co-Targeting BET Proteins and Anti-Apoptotic BCL2 or MCL1 Protein Against AML Blast Progenitor Cells

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BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Synergistic Pre-Clinical Activity of Targeted Inhibition of KDM1A and BET Proteins Against Human AML Blast Progenitor Cells

Mechanisms Underlying Superior Efficacy of Co-Targeting BET Proteins and Anti-Apoptotic BCL2 or MCL1 Protein Against AML Blast Progenitor Cells