Murtaza is a chemical biologist that joined the Gray Lab in July 2021 as a postdoctoral researcher. He developed his love for medicinal chemistry and chemical biology at the undergraduate level at the University of Toronto Mississauga which then motivated him to pursue an MSc (York University, Supervisor: Prof. Edward Lee-Ruff, 2017) and PhD (University of Toronto Mississauga, Supervisor: Patrick T. Gunning, 2021) in the field. His PhD work involved the development of some of the most potent and selective HDAC8 inhibitors known-to-date. It incorporated inhibitors with L-shaped conformational constraints to compliment the L-shaped HDAC8 pocket. His current work at the Gray Lab revolves around the development of first-in-class covalent inhibitors for recently discovered epigenetic targets that have been shown to synergize with anticancer immunotherapy. Additionally, he is interested in developing small-molecule chemoproteomic tools that can potentially expand our ability to target otherwise undruggable proteins, by using protein-protein interactions for cross-labelling/drugging interacting proteins.
Nathanael Gray, Postdoctoral Faculty Sponsor
Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma
JOURNAL OF MEDICINAL CHEMISTRY
2022; 65 (4): 3193-3217
Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role in oncogenic transformation and metastasis. Through a second-generation structure-activity relationship (SAR) study, the design, and biological evaluation of the selective HDAC6 inhibitor NN-390 is reported. With nanomolar HDAC6 potency, >200-550-fold selectivity for HDAC6 in analogous HDAC isoform functional assays, potent intracellular target engagement, and robust cellular efficacy in cancer cell lines, NN-390 is the first HDAC6-selective inhibitor to show therapeutic potential in metastatic Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor often associated with leptomeningeal metastases and therapy resistance. MB stem cells contribute to these patients' poor clinical outcomes. NN-390 selectively targets this cell population with a 44.3-fold therapeutic margin between patient-derived Group 3 MB cells in comparison to healthy neural stem cells. NN-390 demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitro therapeutic potential against Group 3 MB.
View details for DOI 10.1021/acs.jmedchem.1c01585
View details for Web of Science ID 000797940600031
View details for PubMedID 35119267
Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia
JOURNAL OF MEDICINAL CHEMISTRY
2021; 64 (12): 8486-8509
Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.
View details for DOI 10.1021/acs.jmedchem.1c00420
View details for Web of Science ID 000668340800034
View details for PubMedID 34101461
View details for PubMedCentralID PMC8237267
Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype
JOURNAL OF MEDICINAL CHEMISTRY
2021; 64 (5): 2691-2704
Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (Ki = 0.7 nM) and inhibits the enzyme function (IC50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.
View details for DOI 10.1021/acs.jmedchem.0c01922
View details for Web of Science ID 000629166500021
View details for PubMedID 33576627
View details for PubMedCentralID PMC8063965
Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting
JOURNAL OF MEDICINAL CHEMISTRY
2020; 63 (15): 8634-8648
Histone deacetylases (HDACs) are an attractive therapeutic target for a variety of human diseases. Currently, all four FDA-approved HDAC-targeting drugs are nonselective, pan-HDAC inhibitors, exhibiting adverse side effects at therapeutic doses. Although selective HDAC inhibition has been proposed to mitigate toxicity, the targeted catalytic domains are highly conserved. Herein, we describe a series of rationally designed, conformationally constrained, benzanilide foldamers which selectively bind the catalytic tunnel of HDAC8. The series includes benzanilides, MMH371, MMH409, and MMH410, which exhibit potent in vitro HDAC8 activity (IC50 = 66, 23, and 66 nM, respectively) and up to 410-fold selectivity for HDAC8 over the next targeted HDAC. Experimental and computational analyses of the benzanilide structure docked with human HDAC8 enzyme showed the adoption of a low-energy L-shaped conformer that favors HDAC8 selectivity. The conformationally constrained HDAC8 inhibitors present an alternative biological probe for further determining the clinical utility and safety of pharmacological knockdown of HDAC8 in diseased cells.
View details for DOI 10.1021/acs.jmedchem.0c01025
View details for Web of Science ID 000562941200047
View details for PubMedID 32672458
Recent Advances in Chemical Biology Using Benzophenones and Diazirines as Radical Precursors
2020; 25 (10)
The use of light-activated chemical probes to study biological interactions was first discovered in the 1960s, and has since found many applications in studying diseases and gaining deeper insight into various cellular mechanisms involving protein-protein, protein-nucleic acid, protein-ligand (drug, probe), and protein-co-factor interactions, among others. This technique, often referred to as photoaffinity labelling, uses radical precursors that react almost instantaneously to yield spatial and temporal information about the nature of the interaction and the interacting partner(s). This review focuses on the recent advances in chemical biology in the use of benzophenones and diazirines, two of the most commonly known light-activatable radical precursors, with a focus on the last three years, and is intended to provide a solid understanding of their chemical and biological principles and their applications.
View details for DOI 10.3390/molecules25102285
View details for Web of Science ID 000539293400018
View details for PubMedID 32414020
View details for PubMedCentralID PMC7288102
Synthesis of Cyclobutane Analogue 4: Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives
2019; 24 (18)
The coupling of 2-bromo-3-benzoyloxycyclobutanone with purine under basic conditions produces two regioisomers consisting of the N-7 and N-9 alkylated products in equal amounts in their racemic forms. The distribution of the isomers is consistent with the charge delocalization between the N-7 and N-9 positions of the purinyl anion. The structural assignments and relative stereochemistry of each regioisomer were based on 1 and 2D NMR techniques. The relative stereochemistry of the C-2 and C-3 substituents in each regioisomer was the trans orientation consistent with steric factors in the coupling step. The N-9 regioisomer was reduced with sodium borohydride to give the all trans cyclobutanol as the major product in a stereoselective manner. The alcohol was debenzoylated with sodium methoxide in a transesterification step to give the nucleoside analogue. The regioisomeric pyrimidine nucleosides were prepared by Vorbrüggen coupling of the 3-hydroxymethylcyclobutanone triflate with either thymine or uracil followed by stereoselective hydride addition. Regiospecificity of the coupling at the N-1 position was observed and stereoselective reduction to the trans-disubstituted cyclobutanol structure assignments was based on NMR data.
View details for DOI 10.3390/molecules24183235
View details for Web of Science ID 000488830500027
View details for PubMedID 31491981
View details for PubMedCentralID PMC6767184
Crystal structures of the synthetic intermediate 3-[(6-chloro-7H-purin-7-yl)methyl]cyclobutan-1-one, and of two oxetanocin derivatives: 3-[(6-chloro-8,9-dihydro-7H-purin-7-yl)methyl]-cyclobutan-1-ol and 3-[(6-chloro-9H-purin-9-yl)methyl]cyclobutan-1-ol
ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS
2019; 75: 732-+
The crystal structures of an inter-mediate, C10H9ClN4O, 3-[(6-chloro-7H-purin-7-yl)meth-yl]cyclo-butan-1-one (I), and two N-7 and N-9 regioisomeric oxetanocin nucleoside analogs, C10H13ClN4O, 3-[(6-chloro-8,9-di-hydro-7H-purin-7-yl)meth-yl]cyclo-butan-1-ol (II) and C10H11ClN4O, 3-[(6-chloro-9H-purin-9-yl)meth-yl]cyclo-butan-1-ol (IV), are reported. The crystal structures of the nucleoside analogs confirmed the reduction of the N-7- and N-9-substituted cyclo-butano-nes with LiAl(OtBu)3 to occur with facial selectivity, yielding cis-nucleosides analogs similar to those found in nature. Reduction of the purine ring of the N-7 cyclo-butanone to a di-hydro-purine was observed for compound (II) but not for the purine ring of the N-9 cyclo-butanone on formation of compound (IV). In the crystal of (I), mol-ecules are linked by a weak Cl⋯O inter-action, forming a 21 helix along . The helices are linked by offset π-π inter-actions [inter-centroid distance = 3.498 (1) Å], forming layers parallel to (101). In the crystal of (II), mol-ecules are linked by pairs of O-H⋯N hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked by O-H⋯N hydrogen bonds, forming chains along , which in turn are linked by C-H⋯π and offset π-π inter-actions [inter-centroid distance = 3.509 (1) Å], forming slabs parallel to the ac plane. In the crystal of (IV), mol-ecules are linked by O-H⋯N hydrogen bonds, forming chains along . The chains are linked by C-H⋯N and C-H⋯O hydrogen bonds and C-H⋯π and offset π-π inter-actions [inter-centroid distance = 3.364 (1) Å], forming a supra-molecular framework.
View details for DOI 10.1107/S2056989019004432
View details for Web of Science ID 000477632400006
View details for PubMedID 31391955
View details for PubMedCentralID PMC6658957
Synthesis of cyclobutane nucleoside analogues 3: Preparation of carbocyclic derivatives of oxetanocin
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
2018; 37 (9): 518-531
A synthesis of cyclobutene nucleoside analogs in which the nucleobase is tethered by a methylene group is described. The coupling of 6-chloropurine with 3-hydroxymethyl-cyclobutanone proceeds via its triflate to give both N-7 and N-9 regioisomers with relative yields corresponding to the calculated charge distribution of the 6-chloropurinyl anion. The stereoselective reduction of the N-alkylated ketones yielded quantitatively one stereoisomer in each case. The structural assignments were based on spectroscopic data and single crystal X-ray diffraction. Attempts to photoexcite the N-7 and N-9 ketones in order to promote ring-expansion did not ensue. Preliminary evidence suggests a photodecarbonylation to cyclopropanes took place.
View details for DOI 10.1080/15257770.2018.1500697
View details for Web of Science ID 000459975100003
View details for PubMedID 30188772