Mcl-1 inhibitors / Vanderbilt University - LARVOL DELTA

Common and rare variant analyses reveal genetic factors underlying idiopathic pulmonary fibrosis and its shared aetiology with severe COVID-19. (PubMed, EBioMedicine) - "These findings prioritise probable effector genes mediating IPF risk and identify potential therapeutic targets that require validation, with genes colocalising with severe COVID-19 suggesting potential for developing common treatments."

Journal • Hematological Disorders • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • BCL11A • EGF

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model. (PubMed, J Med Chem) - "Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed...The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors."

Journal • Preclinical • B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Oncology • Solid Tumor • BCL2

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors. (PubMed, J Med Chem) - "Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Solid Tumor

Pevonedistat, a Nedd-8 Activating Enzyme Inhibitor, Upregulates NOXA to Increase Effectiveness of Azacitidine and Venetoclax in Preclinical Models of Acute Myelogenous Leukemia (ASH 2019) - P1/2; "VEN has limited efficacy in relapsed-refractory AML as a single agent, but when used in combination with DNA methyltransferase inhibitors (DNMTi; 5’azacitidine-AZA-or decitabine) or low-dose cytosine arabinoside (LDAC), 50-70% of untreated patients in recent clinical trials achieved complete remission (PMID 27520294, 30361262, 30892988)...VEN in combination with selective MCL-1 inhibitors has demonstrated added benefit over either agent alone in AML cells in vitro and in xenograft models but efficacy of this combination in the clinic has yet to be reported (PMID 30185627)... AML cell lines were treated with PEV, AZA and VEN alone, and compared with various VEN/PEV/AZA combinations revealing improved combinatorial activity with the triplet in the majority of cell lines and associated NOXA induction. Similar results were seen in primary AML patient samples ex vivo (Figure 1). These combinations were compared in vivo in an OCI-AML2 cell line xenograft model, also..."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

PTPN11 Mutations Confer Unique Metabolic Properties and Increase Resistance to Venetoclax and Azacitidine in Acute Myelogenous Leukemia (ASH 2018) - P1b; "Previous studies have demonstrated the importance of energy metabolism as it relates to numerous aspects of leukemia stem cell (LSC) biology. The presence of PTPN11 mutations represents both a novel method for predicting response to ven/aza and a potential strategy for targeting patients who progress. We propose that addition of an MCL-1 inhibitor for treatment of AML patients bearing PTPN11 or related mutations may increase therapeutic responses."

IO biomarker • Acute Myelogenous Leukemia • Biosimilar • Breast Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Selective inhibition of MCL1 overcomes venetoclax-resistance in a murine model of myelodysplastic syndromes. (PubMed, Haematologica) - "Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN+MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • BCL2 • BCL2L1

[VIRTUAL] Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer (AACR-II 2020) - "Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo...To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours...Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer."

Clinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EPHA2

Developmental Plasticity of Acute Myeloid Leukemia Mediates Resistance to Venetoclax-Based Therapy (ASH 2019) - "To initially address this question, we retrospectively reviewed 75 newly diagnosed AML patients who received venetoclax + azacitidine (VEN+AZA) at our institution and analyzed several baseline clinical features to determine the ability of each to predict disease that was refractory to treatment (defined as a lack of complete remission [CR], CR with incomplete recovery of peripheral blood counts [CRi], partial remission, or morphological leukemia free state [MLFS])...Using colony-forming and xenograft assays, we show the stem and progenitor potential of monocytic AMLs are selectively more sensitive to MCL-1 inhibition comparing to BCL-2 inhibition...Based on these findings, we propose that AML exists on a developmental spectrum that is inherently fluid, where with appropriate selective pressure the disease can acquire characteristics of a more differentiated state. Further, our data indicate that optimal AML therapy will require strategies designed to target both..."

ITGAM

Variable Response to BCL2 Inhibition in MDS Is Enhanced across MDS Subtypes with Synergistic Combination of BCL2+MCL1 Inhibition (ASH 2019) - "Venetoclax (VEN), a newly FDA-approved therapy that specifically inhibits the anti-apoptotic protein BCL2, has yielded response rates of up to 50-70% in elderly AML including impressive responses in transformed MDS which previously failed DNMTi (DiNardo et al, 2019, Wei et al, 2019)...Interestingly, nearly all MDS subtypes were sensitive to the selective MCL1 inhibitor, S63845...Moreover, drug synergy can be obtained across all subtypes of MDS by combining BCL2 and MCL1 inhibitors. BCL2 inhibition is changing the standard of care in AML, thus, refining the design of clinical trials testing BCL2 and MCL1 inhibitors in MDS and the precision of patient selection for therapy is a great priority."

IO Biomarker • BCL2L1

Predicting MCL1 inhibitor sensitivity in large cell line panels using a gene expression signature (AACR 2019) - "Moreover, solid tumor samples in contrast to solid tumor cell lines are predicted to be broadly sensitive to MCL1 inhibition with a predicted anti-tumor effect rate of 60% to 95%. In summary, our work describes the translational challenges using cell line-derived predictors on ex vivo tumor samples."

IO Biomarker