On April 25, 2025 Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting for its highly selective IV SMARCA2 degrader and its highly selective KAT6A degraders (Press release, Prelude Therapeutics, APR 25, 2025, View Source [SID1234652149]).

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Peggy Scherle, Ph.D., Chief Scientific Officer of Prelude, stated, "We are pleased to provide further preclinical data on the discovery of our lead selective SMARCA2 degrader PRT3789, currently advancing in early clinical development for patients with SMARCA4 mutated cancers. We are also delighted to report initial preclinical data from our selective KAT6A degrader discovery program. These data demonstrate that selectively degrading KAT6A results in robust anti-cancer activity in various pre-clinical models of breast cancer and other solid tumors. We believe that our first-in-class, highly potent KAT6A selective degraders have the potential to expand the therapeutic reach of KAT6A/B inhibitors currently advancing in the clinic, while addressing safety challenges associated with non-selective approaches to this clinically validated target."

Details on the presentations are as follows:

Title: Elucidating the Molecular Mechanism of Action of the First-in-Human SMARCA2 Selective Degrader PRT3789

Summary:

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PRT3789 is a first-in-human SMARCA2 degrader that selectively induces deep and sustained SMARCA2 degradation in preclinical and clinical studies.
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PRT3789 achieves high selectivity by inducing a more stable ternary complex between SMARCA2 and VHL than SMARCA4 and VHL.

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K1405 loop in SMARCA2 provides a unique lysine residue to enable selective ubiquitination and also stabilizes the SMARCA2:PRT3789:VHL complex.
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SMARCA2 resynthesis rate is 2-3 times slower than SMARCA4 thereby enhancing the selectivity profile and contributing to the broad therapeutic index and favorable safety profile observed with PRT3789 in clinical studies to date.
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PRT3789 is currently under evaluation in Phase 1 and Phase 2 studies in patients with advanced solid tumors with loss of SMARCA4 (NCT05639751 and NCT06682806).

Link: Publications – Prelude Therapeutics (preludetx.com)

Title: Discovery of First-in-Class Potent and Selective Oral Degraders of KAT6A that Demonstrate Anti-cancer Activity in Pre-clinical Models

Summary:

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KAT6A expression is associated with cancer growth and is recurrently amplified in breast, lung, ovarian and other cancers.1
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KAT6 is a clinically validated target with a dual KAT6A/B inhibitor recently demonstrating promising efficacy in heavily pre-treated patients with ER+/HER2- breast cancer, albeit with potential on-target safety considerations including neutropenia.2
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Prelude hypothesized that a targeted protein degradation approach could enable discovery of KAT6A selective candidates with potential for improved hematological safety and more robust single agent activity relative to other KAT6-targeted approaches.
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Prelude believes that it has identified a series of first-in-class, sub-nanomolar, selective and readily orally bioavailable KAT6A degraders now advancing to candidate nomination.
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Pre-clinical data presented demonstrate that Prelude’s selective KAT6A degraders:
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Drive significantly deeper anti-cancer responses compared to non-selective KAT6A/B inhibitors across multiple KAT6A-amplified tumors.
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Disrupt the histone acetyltransferase (HAT) complex resulting in a deeper biological effect on ERα expression.
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Show sustained activity in ESR1- and Pi3Kalpha-mutated cells, as well as endocrine therapy- and CDK4/6i-resistant cells.
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Exhibit robust combination benefit with SoC and potential synergy with next generation breast cancer therapies.
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Deliver robust in vivo target engagement and deep tumor regressions, including complete regressions, in breast and lung cancer xenografts as a monotherapy at low oral daily doses.
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Display reduced hematologic toxicity compared to KAT6A/B inhibitors.