Search

Your search keyword '"Ahmed Mamai"' showing total 2 results
Start Over Author "Ahmed Mamai" Language english
2 results on '"Ahmed Mamai"'

1. Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

Author

Mark F. Mabanglo, Brian Wilson, Mahmoud Noureldin, Serah W. Kimani, Ahmed Mamai, Chiara Krausser, Héctor González-Álvarez, Smriti Srivastava, Mohammed Mohammed, Laurent Hoffer, Manuel Chan, Jamie Avrumutsoae, Alice Shi Ming Li, Taraneh Hajian, Sarah Tucker, Stuart Green, Magdalena Szewczyk, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Suzanne Ackloo, Peter Loppnau, Yanjun Li, Almagul Seitova, Taira Kiyota, Jue George Wang, Gilbert G. Privé, Douglas A. Kuntz, Bhashant Patel, Vaibhavi Rathod, Anand Vala, Bhimsen Rout, Ahmed Aman, Gennady Poda, David Uehling, Jailall Ramnauth, Levon Halabelian, Richard Marcellus, Rima Al-awar, and Masoud Vedadi

Subjects
Science
Abstract

Abstract Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates.

Published
2024
Full Text
View/download PDF

2. Leveraging an open science drug discovery model to develop CNS penetrant ALK2 inhibitors for the treatment of diffuse intrinsic pontine glioma

Author

Kurumi Y. Horiuchi, Roslin Adamson, Ahmed Aman, Ahmed Mamai, Soyoung Kim, Haiching Ma, Sue Cramp, Taira Kiyota, Alex N. Bullock, David Uehling, Jeff A O'Meara, Eleanor Williams, Methvin Isaac, J Nicole Hamblin, Ekaterina Kuznetsova, Julie Owen, David McLeod, Jong Fu Wong, Gennady Poda, David Smil, Owen G Roberts, Aled M. Edwards, Alison Howarth, Brian J. Wilson, and Rima Al-awar

Subjects
Male, Open science, medicine.medical_treatment, Antineoplastic Agents, Mice, SCID, 01 natural sciences, Rats, Sprague-Dawley, Structure-Activity Relationship, 03 medical and health sciences, Pharmacokinetics, In vivo, Drug Discovery, medicine, Animals, Humans, Protein Kinase Inhibitors, 030304 developmental biology, 0303 health sciences, Molecular Structure, Drug discovery, Chemistry, Diffuse Intrinsic Pontine Glioma, Activin receptor, Pediatric cancer, 0104 chemical sciences, Radiation therapy, 010404 medicinal & biomolecular chemistry, HEK293 Cells, Tolerability, Cancer research, Molecular Medicine, Female, Activin Receptors, Type I
Abstract

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

Published
2020

Catalog

Books, media, physical & digital resources
See catalog results