Biology subjects

McDougal, D. P.

Publications and source records attributed to McDougal, D. P..

3 recordsLinked to original sources

bioRxiv2025

The STAMP inhibitor asciminib is a new treatment option for ABL-rearranged ALL revealing a novel role for the 5' fusion partner in determining drug response

ABL-rearranged (ABLr) acute lymphoblastic leukaemia (ALL) is associated with high rates of treatment failure and relapse and novel treatments are required. We investigated activity of the STAMP inhibitor asciminib in non-BCR::ABL1 ABLr ALL. The most common fusion in ABLr ALL is NUP214::ABL1, which is associated with aggressive disease. For the first time we establish asciminib activity in three pre-clinical patient derived xenograft models of NUP214::ABL1 ALL. Treatment with asciminib reduced NUP214::ABL1 leukaemic burden, splenomegaly and ABL1 kinase activation. We observed significantly increased survival outcomes in asciminib-treated versus control mice. Additionally, site directed mutagenesis, in vitro cell death assays and in silico structural modeling defined a region of the ABL1 SH3 domain critical for asciminib efficacy and necessary for mediation of allosteric inhibition. Our findings establish asciminib as a potential treatment for NUP214::ABL1 ALL, significantly expanding the number of ALL patients who may benefit from asciminib therapy which has an excellent safety and tolerability profile.

cancer biology↗

bioRxiv2025

A ternary switch determines ERα LBD conformation

The transcription factor estrogen receptor (ER) is the primary driver of ER+ breast cancer progression and a target of multiple FDA-approved anticancer drugs. Ligand-dependent activity of ER is determined by the conformation of helix-12 (H12) within the ligand binding domain (LBD), but how H12 transitions from an unliganded (apo) state to active (estrogen-bound) or inactive (SERM/SERD-bound) states remains unresolved. Here, we present the first crystal structure of an apo ER LBD, revealing a third distinct H12 conformation that regulates receptor activity. Structural mass-spectrometry, small-angle X-ray scattering, functional analysis and molecular dynamics simulations reveal that the apo conformation of H12 is stable in the absence of ligand, but is destabilised by Y537S and D538G breast cancer mutations driving constitutive activation. We propose a model in which H12 functions as a ternary molecular switch to determine receptor activity. These findings provide critical insights into the ligand-dependent and -independent regulation of ER and have significant implications for therapeutic intervention.

biochemistry↗

bioRxiv2025

Structural evolution of the estrogen receptor regulatory domain

Estrogen receptors (ERs) , {beta} and {gamma} are ligand-dependent transcription factors that regulate vertebrate reproduction, cell survival and other physiological processes. Here, we report an integrative analysis of mammalian and teleost receptors, including the first structure of an ER{gamma} ligand binding domain (LBD), showing that structural divergence acquired during evolution is accommodated by different strategies within functional regions to preserve intrinsic regulatory mechanisms. Supervised-learning and comparative Markov modelling uncover highly constrained network structures essential for allostery and protein folding, revealing a fundamental regulatory architecture and source of selective pressure in ER+ breast cancer and reproductive disorders. Finally, cross-referencing molecular constraints to genome sequencing reveal evolutionary origins underlying natural genetic variation in humans and widespread disruption of constraints. This work provides structural insights into the conservation of gene regulation by essential transcription factors and has implications for precision medicine.

biochemistry↗