A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)

Johnson, Christopher N.; Ahn, Jong Sook; Buck, Ildiko M.; Chiarparin, Elisabetta; Day, James E. H.; Hopkins, Anna; Howard, Steven; Lewis, Edward J.; Martins, Vanessa; Millemaggi, Alessia; Munck, Joanne M.; Page, Lee W.; Peakman, Torren M.; Reader, Michael; Rich, Sharna J.; Saxty, Gordon; Smyth, Tomoko; Thompson, Neil T.; Ward, George A.; Williams, P.; Wilsher, Nicola E.; Chessari, Gianni

doi:10.1021/acs.jmedchem.8b00900

Cited by 45 publications

(32 citation statements)

References 27 publications

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“…ASTX660 is a novel, potent, nonpeptidomimetic, small-molecule antagonist of both cIAP1/2 and XIAP, which was discovered using fragment-based drug design (7)(8)(9)(10). ASTX660 inhibited intracellular degradation of cIAP1 in human breast cancer MDA-MB-231 cells with a half maximal inhibitory concentration of 0.22 nM and blocked XIAP in a cellular XIAP-caspase 9 immunoprecipitation assay with a half maximal inhibitory concentration of 2.8 nM (8). ASTX660 inhibited proliferation and induced apoptosis in multiple cancer cell lines; these effects were dependent on the presence of an inflammatory stimulus (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma

Mita

LoRusso

Papadopoulos

et al. 2020

Clinical Cancer Research

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Purpose: This first-inhuman , phase 1 study evaluated ASTX660, an oral, smallmolecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Experimental Design: ASTX660 was administered orally once daily on a 7-day-on/7day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Dose expansion was conducted at the RP2D. Results: Forty-five patients received ASTX660 (range 15-270 mg/d). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/d and 1 patient at 210 mg/d. The maximum tolerated dose was determined to be 210 mg/d and the RP2D 180 mg/d. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at ~0.5-1.0 hour. An ~2-fold accumulation in area under the curve exposures was observed on day 7 vs 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/d RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma. Conclusions: ASTX660 demonstrated a manageable safety profile, and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/d RP2D.

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Section: Introductionmentioning

confidence: 99%

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma

Mita

LoRusso

Papadopoulos

et al. 2020

Clinical Cancer Research

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“…Experimental structures of the XIAP-BIR3 domain in different complexes with embelin, Smac or Smac mimetics and non-peptidomimetics small molecules, revealed that residues GLY306, THR308, GLU314, TRP323 and TYR324 are crucial residues involved in the interaction with the BIR3 domain of XIAP [35,41,86,89]. The results of the docking experiments show a possible binding mode for gibbilimbol B, eriopodol A, and erioquinol.…”

Section: Resultsmentioning

confidence: 99%

XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death

Muñoz

Brucoli

Zecchini

et al. 2019

Cancers

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X-linked inhibitor of apoptosis protein (XIAP) is an emerging crucial therapeutic target in cancer. We report on the discovery and characterisation of small organic molecules from Piper genus plants exhibiting XIAP antagonism, namely erioquinol, a quinol substituted in the 4-position with an alkenyl group and the alkenylphenols eriopodols A–C. Another isolated compound was originally identified as gibbilimbol B. Erioquinol was the most potent inhibitor of human cancer cell viability when compared with gibbilimbol B and eriopodol A was listed as intermediate. Gibbilimbol B and eriopodol A induced apoptosis through mitochondrial permeabilisation and caspase activation while erioquinol acted on cell fate via caspase-independent/non-apoptotic mechanisms, likely involving mitochondrial dysfunctions and aberrant generation of reactive oxygen species. In silico modelling and molecular approaches suggested that all molecules inhibit XIAP by binding to XIAP-baculoviral IAP repeat domain. This demonstrates a novel aspect of XIAP as a key determinant of tumour control, at the molecular crossroad of caspase-dependent/independent cell death pathway and indicates molecular aspects to develop tumour-effective XIAP antagonists.

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“…1). 8–10 Modification of this initial fragment hit (1) along the C(sp 3 )–H growth vectors resulted in a potent elaborated lead compound, AT-IAP (2). However, during the F2L process, methods for direct functionalization of the native fragment (and related intermediates) were not available.…”

Section: Introductionmentioning

confidence: 99%

Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

Grainger¹,

Heightman²,

Ley

et al. 2019

Chem. Sci.

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Cited by 45 publications

References 27 publications

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma

A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma

XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death

Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

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