Christian Atsriku

Discovery of 2H-Pyrrolo[3,4- c ]pyridin-3-one Derivatives as Type-III c-MET Inhibitors Enabled by Free-Energy Perturbation Calculations

Éric Therrien, Shulu Feng, Katherine Amberg-Johnson, Nadim Shaikh et autres

The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET wild-type (WT) potency, selectivity over other kinases, and brain penetration. Here, we report a …

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Structure-Based Discovery of Imidazo[4,5- c ]pyridine SARM1 Modulators Showing Paradoxical Activation

Steven K. Albanese, Brittany E. Hopkins, Andrea M. Olland, Alexis Fairman et autres

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Abstract 4376: Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors

Hui Wang, Felicia Gray, Christian Atsriku, Adam M. Levinson et autres

Abstract KRAS is the most frequently mutated oncogene in many tumor types including pancreatic (90%), colorectal (50%) and lung cancers (30%). KRAS mutation typically impairs the conversion of active GTP-bound KRAS to the inactive GDP-bound form, resulting in constitutively active KRAS. SOS1 …

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Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations

Abba E. Leffler, Evelyne M. Houang, Felicia Gray, Andrew T. Placzek et autres

Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues …

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Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform

Hideyuki Igawa, Zef A. Könst, Éric Therrien, Mee Y. Shelley et autres

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and …

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Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using in silico Enabled Drug Discovery Platform

Hideyuki Igawa, Zef A. Könst, Éric Therrien, Mee Y. Shelley et autres

Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment of non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to the …

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Sgr-2921, a Potent CDC7 Inhibitor, Demonstrates Significant Anti-Leukemic Responses in Patient-Derived AML Models Representing Difficult-to-Treat Disease

Hooman Izadi, Hui Wang, Christian Atsriku, Zef Konst et autres

Introduction: Elevated replication stress (RS) is a common feature of many highly proliferative cancers including AML. CDC7 has been shown to activate key components of the RS response, including ATR, and the BRCA1 and cohesin complexes, thereby mitigating accumulation of DNA damage …

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Inhibition of CDC7 with Sgr-2921 in AML Models Results in Enhanced DNA Damage and Anti-Leukemic Activity As Monotherapy and in Combination with Standard of Care Agents

Lyuben M. Tsvetkov, Janét Pittsenbarger, Christian Atsriku, Paul Devine et autres

Introduction: CDC7 is a protein kinase that is active during the S-phase of the cell cycle. CDC7 plays a critical role in the replication stress response by phosphorylation and activation of the BRCA1 and Cohesin complexes, which protect and restart stalled replication …

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Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects

Allison M. Gaudy, Christian Atsriku, Ying Ye, Kimberly MacGorman et autres

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Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase-2 inhibitor enasidenib in rats and humans

Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang et autres

C]enasidenib to rats (10 mg/kg; 100 μCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95-99% of …

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Assessment of drug–drug interaction potential and PBPK modeling of CC-223, a potent inhibitor of the mammalian target of rapamycin kinase

Zeen Tong, Rangaraj Narayanan, Christian Atsriku, Jim Nissel et autres

1. CC-223 was studied in vitro for metabolism and drug–drug interactions (DDI), and in clinic for interaction with ketoconazole.2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3) and imine (M13), with M1 being the most prominent …

Absorption, distribution, metabolism, and excretion of mTOR kinase inhibitor CC-223 in rats, dogs, and humans

Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang et autres

C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg), and healthy volunteers (20 mg; 200 nCi). 2. CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans …