Md Abdullah Al Noman

All Publications

• The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue. Cell chemical biology Hinshaw, S. M., Yuan, L., Noman, M. A., Martinez, M. J., Colombo, G. M., Dwyer, B. G., Ji, W., Romero, B. A., Forrest, I., Lu, J., Bian, J., Dunn, T. B., Garvin, E. R., Fernandez, D., Zhang, T., Gray, N. S., Corsello, S. M. 2026

  Abstract

  Molecular glues that induce new protein interactions can be potent therapeutics. We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase. PRLX causes TRIM21 to bind the nuclear pore protein NUP98, triggering nuclear pore complex (NPC) degradation. We present here the structural and biochemical basis of NUP98 recognition, finding that ternary complex assembly depends on the creation of a composite TRIM21-small molecule surface competent for NUP98 binding. A scarcity of direct small molecule-NUP98 contacts likely explains how multiple structurally diverse TRIM21 ligands can induce NPC degradation. We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities.

  View details for DOI 10.1016/j.chembiol.2026.04.016

  View details for PubMedID 42202785

• From Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha (vol 69, pg 1568, 2026) JOURNAL OF MEDICINAL CHEMISTRY Shi, R., Al Noman, M., Mannowetz, N., Cheryala, N., Haque, E., Taher, N., Maitra, S., Naqvi, T., Chung, S. S. W., Bakshi, A., Hawkinson, J. E., Wong, H. L., Wolgemuth, D. J., Georg, G. I. 2026; 69 (5): 6295

  View details for DOI 10.1021/acs.jmedchem.6c00520

  View details for Web of Science ID 001706048700001

  View details for PubMedID 41773782

  View details for PubMedCentralID PMC12990025

• From Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha JOURNAL OF MEDICINAL CHEMISTRY Shi, R., Al Noman, M., Mannowetz, N., Cheryala, N., Haque, E., Maitra, S., Naqvi, T., Chung, S. S. W., Bakshi, A., Hawkinson, J. E., Wong, H. L., Wolgemuth, D. J., Georg, G. I. 2026

  Abstract

  The retinoic acid receptor alpha (RARα) has emerged as a compelling genetically and pharmacologically validated target for nonhormonal male contraception due to its essential role in spermatogenesis. In the present study, a search for specific inhibitors of RARα utilized systematic linker bioisosterism, hydrophobic core modification, and iterative structure-activity relationship refinement, identified the acid 9, a pyrrole-linked analog that potently inhibits RARα (IC50 = 1.2 nM) with >300-fold selectivity over RARβ and RARγ. Sprague-Dawley rat studies with the sodium salt of 9, YCT-529, showed good oral bioavailability and dose-proportional pharmacokinetics without drug accumulation after 28 days of dosing. Once-daily oral administration (0.75 mg/kg for 28 days) reversibly suppressed epididymal sperm counts and fertility in rats, with a no-observed-adverse-effect level at 30 mg/kg (highest dose tested), affording a ≥40-fold therapeutic window. These findings validated aromatic linker substitution as a powerful design strategy for identifying RARα antagonists and led to the clinical advancement of YCT-529 as a nonhormonal male contraceptive.

  View details for DOI 10.1021/acs.jmedchem.5c03051

  View details for Web of Science ID 001660633500001

  View details for PubMedID 41524264

• Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Al Noman, M., Cuellar, R. A. D., Kyzer, J. L., Chung, S. S. W., Cheryala, N., Holth, T. A. D., Maitra, S., Naqvi, T., Wong, H. L., Schonbrunn, E., Hawkinson, J. E., Wolgemuth, D. J., Georg, G. I. 2023; 261: 115821

  Abstract

  Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with significant oral bioavailability, metabolic stability, and testes exposure. Compound 21 was evaluated for its effects on spermatogenesis and disruption of fertility in a mouse model. Oral administration of compound 21 at low doses showed reproducibly characteristic albeit modest effects on spermatogenesis, but no effects on fertility were observed in mating studies. The inhibition of spermatogenesis could not be enhanced by raising the dose and lengthening the duration of dosing. Thus, 21 may not be a good candidate to pursue further for effects on male fertility.

  View details for DOI 10.1016/j.ejmech.2023.115821

  View details for Web of Science ID 001097444100001

  View details for PubMedID 37776573

  View details for PubMedCentralID PMC10841505

• Investigation of selective retinoic acid receptor alpha antagonist ER-50891 and related analogs for male contraception ARCHIV DER PHARMAZIE Kyzer, J. L., Al Noman, M., Cuellar, R. A. D., Chung, S. S. W., Maitra, S., Naqvi, T., Hawkinson, J. E., Wolgemuth, D. J., Georg, G. I. 2023; 356 (7): e2300031

  Abstract

  Retinoic acid receptor alpha (RARα) antagonist ER-50891 and 15 analogs were prepared and tested in vitro for potency and selectivity at RARα, RARβ, and RARγ using transactivation assays. Minor modifications to the parent molecule such as the introduction of a C4 tolyl group in place of the C4 phenyl group on the quinoline moiety slightly increased the RARα selectivity but larger substituents significantly decreased the potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond produced inactive compounds. ER-50891 was found to be stable in male mouse liver microsomes and was tested in male mice to assess its effects on spermatogenesis. Characteristic, albeit modest and transient, effects on spermatogenesis were observed.

  View details for DOI 10.1002/ardp.202300031

  View details for Web of Science ID 000982849800001

  View details for PubMedID 37154197

  View details for PubMedCentralID PMC13243132

• Retinoic acid receptor antagonists for male contraception: current status BIOLOGY OF REPRODUCTION Al Noman, M., Kyzer, J. L., Chung, S. S. W., Wolgemuth, D. J., Georg, G. 2020; 103 (2): 390-399

  Abstract

  Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure-activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.

  View details for DOI 10.1093/biolre/ioaa122

  View details for Web of Science ID 000592978700026

  View details for PubMedID 32671394

  View details for PubMedCentralID PMC7401398

• Crispenes F and G, <i>cis</i>-Clerodane Furanoditerpenoids from <i>Tinospora crispa</i>, Inhibit STAT3 Dimerization JOURNAL OF NATURAL PRODUCTS Al Noman, M., Hossain, T., Ahsan, M., Jamshidi, S., Hasan, C., Rahman, K. 2018; 81 (2): 236-242

  Abstract

  Two new cis-clerodane-type furanoditerpenes, crispenes F and G (1 and 2), together with seven known compounds, were isolated from the stems of Tinospora crispa. Crispenes F and G (1 and 2) inhibited STAT3 dimerization in a cell-free fluorescent polarization assay and were found to have significant cytotoxicity against a STAT3-dependent MDA-MB 231 breast cancer cell line, while being inactive in a STAT3-null A4 cell line. These two compounds share structural similarities with a previously reported STAT3 inhibitor, crispene E, isolated from the same plant. Molecular docking studies suggested that the molecules inhibit STAT3 by interacting with its SH2 domain.

  View details for DOI 10.1021/acs.jnatprod.7b00377

  View details for Web of Science ID 000426618300003

  View details for PubMedID 29397715