Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Radiological outcome of innocent infant hip clicks.

Radiographic follow-up is questioned for infants with hip clicks who have normal results from ultrasound scan examination of the hips. Infants whose sole risk factor for developmental dysplasia of the hip was a soft tissue hip click who had a normal ultrasound scan on initial assessment were identified. A follow-up 6-month pelvis radiograph was assessed. The acetabular index, position of femoral ossific nucleus and Shenton's line were measured. Rotated radiographs were excluded. One hundred and seventy-one infants (193 clicking hips) met the criteria for inclusion. All parameters measured were within normal ranges. In this study infants with hip clicks and a normal hip ultrasound scan on initial assessment had a normal radiograph at 6 months.