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Tisi et al., Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives, ACS Chem. Biol., 2016, 11 (11), pp 3093–3105, DOI: 10.1021/acschembio.6b00308

Abstract The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using […]

Johnson et al., Fragment-to-Lead Medicinal Chemistry Publications in 2015, J. Med. Chem., 2017, 60 (1), pp 89–99, DOI: 10.1021/acs.jmedchem.6b01123

Abstract Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will […]

Woolford et al., Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), J. Med. Chem., 2016, 59 (23), pp 10738–10749, DOI: 10.1021/acs.jmedchem.6b01427

Abstract Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in […]

Lebraud et al. “Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras.” ACS Cent. Sci.,2016, 2 (12), pp 927–934 DOI:10.1021/acscentsci.6b00280

Summary Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization […]

Astex to Showcase Its Next-Generation Hypomethylating Agents Being Developed for Treatment of AML/MDS at the 2016 Annual Meeting of the American Society of Hematology

New clinical data to be presented in four oral presentations on guadecitabine (SGI-110) and ASTX727 Two new global Phase 3 studies commencing to investigate the potential of guadecitabine in the treatment of relapsed / refractory AML (ASTRAL-2) and relapsed / refractory MDS (ASTRAL-3) Enrollment completed into the global Phase 3 clinical study of guadecitabine in […]

2016 EHA: OS and subgroup results from randomized Phase 2 study of SGI-110 in previously treated MDS

Summary Guadecitabine (SGI-110) is a next generation hypomethylating agent (HMA) designed as a dinucleotide of decitabine and deoxyguanosine that is resistant to deamination by cytidine deaminase (CDA). This results in a prolonged in vivo exposure to decitabine following small volume subcutaneous (SC) administration of guadecitabine. Safety and clinical activity in resistant MDS and AML have […]

2016: Addition of onalespib to crizotinib prior to progression in pts with ALK-pos NSCLC: P2 Results

Summary Hsp90 is required for proper ALK function Onalespib (AT13387) is a second generation Hsp90 inhibitor Onalespib in ALK-driven pre-clinical models: Displays potent antitumor activity Delays the onset of resistance In the clinic, onalespib  Has a safety profile consistent with the class (diarrhea, mild transient visual changes) PK & PD results support weekly dosing – […]

2016 AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

Summary Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine loops that can contribute to survival and reduction of paclitaxel-induced apoptosis in cancer cells. One of the mechanisms of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs). Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-B activation, blocking […]

2016 EHA: Phase 1 dose-escalation study of ASTX727: comparable variability in pharmacokinetics

Summary Hypomethylating agents (HMA) are typically administered parenterally and adjusted to body surface area (BSA) in order to achieve target pharmacokinetic (PK) parameters associated with response. Much of the variation associated with administration of HMAs is related to the intrinsic activity of cytidine deaminase (CDA) an enzyme which rapidly metabolizes HMAs and is highest in […]

2016 ASCO: Epigenetic resensitization in recurrent, platinum-resistant OC using SGI-110: Phase 2 results

Summary In the past 20 years there has been little change in the 1-, 3-, and 5-year survival rates for patients with ovarian cancer. 5-year survival is ~25% for patients diagnosed with advanced stage disease Recurrence is common and patients develop resistance to chemotherapy Platinum resistant ovarian cancer is uniformly fatal and epigenetic changes have […]