Abstract The discovery and characterisation of AMX-883, an orally bioavailable, highly potent and selective degrader of Bromodomain-containing protein 9 (BRD9) will be described. Acute myeloid leukaemia (AML) is commonly characterized by a block in the differentiation of myeloid progenitors, preventing their maturation and resulting in the proliferation of immature myeloid blasts. Therapies which remove the differentiation block and allow maturation of AML blasts have demonstrated clinical benefit in several sub-populations of AML; these include all-trans retinoic acid, isocitrate dehydrogenase inhibitors, and most recently menin inhibitors. Bromodomain containing protein 9 (BRD9) is a subunit of the non-canonical BAF complex where it plays a key structural and functional role linked to regulation of chromatin structure and maintaining genomic stability in AML. Recent published data illustrates a key regulatory role for BRD9 in maintaining AML myeloid cell stemness, and the loss of BRD9 expression suppresses development and survival of leukemic blasts. The optimisation of a novel class of BRD9 protein degrader, acting via the E3 ligase DCAF16, has resulted in an orally bioavailable clinical candidate, AMX-883, with sub nanomolar potency and exquisite selectivity over related bromodomain proteins. The DCAF16 and ubiquitin proteosome-based mechanism of action of AMX-883 was further validated by a high resolution Cryo-EM ternary complex structure of BRD9: DCAF16: AMX-883. RNA-sequencing studies reveal that BRD9 degradation by AMX-833 results in the induction of genes associated with myeloid differentiation, and repression of genes that promote cell proliferation. BRD9 maintains the differentiation block, in part through the expression of key hematopoietic transcription factors, including MYC, IRF8 and MYB. Furthermore, AMX-883 increases markers of maturation and differentiation, including CD11b, CD86 and CD14, across a range of AML cell lines representing diverse cytogenetic backgrounds, including TP53 mutations. In vivo AMX-883 demonstrated degradation of BRD9 and induction of differentiation cell line-derived xenograft (CDX) models. In patient derived xenograft (PDX) models, AMX-883 significantly reduced leukemic burden in bone marrow and blood over the treatment period and resulted in a significant increase in survival. Combination of AMX-883 with venetoclax resulted in synergistic efficacy in AML cell lines. In vivo data supporting clinically relevant combination therapies will be presented. Our data establishes a pivotal role for BRD9 for the treatment of AML, an area of high unmet need, particularly for therapies complementary to the standard anti-proliferative agents. AMX-883 is planned to commence a First-in-Human clinical study in AML patients during 2026. Citation Format: Martin Pass. Discovery of AMX-883: an orally bioavailable, novel degrader of BRD9 as a karyotype-independent pro-differentiation agent for the potential treatment of AML abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND10.
Martin Pass (Fri,) studied this question.
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