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Ref Type Abstract
Authors Anke Klippel; Rui Wang; Loredana Puca; Andrew Lee Faber; Weihua Shen; Shripad V. Bhagwat; Kannan Karukurichi; Feiyu Fred Zhang; Carmen Perez; Ramon Rama; Ana Ramos; Yi Zheng; Zahid Bonday; James Thomas; Harold B. Brooks; Lisa J. Kindler; Sarah M. Bogner; Parisa Zolfaghari; Mark Hicks II; Sophie Callies; Brian Mattioni; Laurie LeBrun; Jim Durbin; Erin Anderson; Chris Mayne; Edward Kesicki; Gabrielle Kolakowski; Steven W. Andrews; Barbara J. Brandhuber
Title Preclinical characterization of LOX-22783, a highly potent, mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor
Abstract Text Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of advanced breast cancers. While there is one PI3Kα inhibitor FDA-approved for patients with PI3Kα-mutated breast cancer, and many others in clinical development, all of these agents inhibit wild-type PI3Kα and its mutated form with approximate equal potency. As a result, their efficacy is limited by toxicities associated with on target wild-type PI3Kα inhibition, notably hyperglycemia as well as cutaneous and GI toxicity. LOX-22783 is a highly potent, mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor. Here, we describe the preclinical profile of LOX-22783. H1047R selectivity was measured using biochemical kinase activity and cell-titer Glo and signal transduction assays. Tumor growth inhibition, pharmacokinetic and pharmacodynamic effects were assessed in in vivo studies using xenograft and patient-derived xenograft (PDX)-models. LOX-22783 inhibited growth and signaling responses in multiple H1047R-driven breast cancer cell lines and demonstrated high selectivity for H1047R mutated PI3Kα (EC50 values <5 nM) relative to wild-type PI3Kα (EC50 >250 nM) as well as the other wild-type PI3K isoforms (beta, gamma, and delta, all EC50 >250nM). In enzyme and cell-based assays, LOX-22783 dissociated from PI3Kα H1047R at a slower rate (3-6 hrs) compared to alpelisib (≤10 mins), potentially allowing for extended inhibition of PI3Kα H1047R by LOX-22783. LOX-22783 also normalized the EGF-stimulated membrane-localization of PI3Kα H1047R while alpelisib did not. LOX-22783 was highly kinome-selective when assayed at 3 µM, with no inhibitory activity on 17 lipid kinases or 374 protein kinases. In preclinical species, LOX-22783 demonstrated high oral bioavailability, including exposure in the CNS, a common site of metastases for patients with breast cancer. In vivo, LOX-22783 demonstrated dose-dependent tumor regression in H1047R breast cancer models without inducing hyperglycemia or other toxicities. Tumor pharmacodynamic analyses confirmed successful pathway inhibition. At doses resulting in 90% pathway inhibition, tumor regressions of ≥60% were observed. This wide therapeutic index is predicted to allow for maximizing dose intensity and efficacy in patients, without wild-type PI3Kα inhibition limiting target coverage for the H1047R mutant form. These data demonstrate that LOX-22783 potently and selectively inhibits mutant H1047R, but not wild-type PI3Kα, or other PI3K isoforms. LOX-22783 binds to an allosteric pocket distinct from the ATP binding site used by the approved and investigational PI3Kα inhibitors. We hypothesize that this profile will lead to differentiated efficacy and tolerability for patients with PI3Kα H1047R-mutated cancers, with the additional potential to address brain metastases. An IND submission is planned for 2022.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
LOXO-783 LOXO-783 1 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
LOXO-783 LOXO 783|LOXO783|LOX-22783|LOX 22783|LOX22783 PIK3CA inhibitor 23 LOXO-783 (LOX-22783) selectively inhibits PIK3CA H1047R leading to decreased downstream signaling and potentially resulting in tumor growth inhibition (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P142).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA H1047R breast cancer predicted - sensitive LOXO-783 Preclinical - Pdx & cell culture Actionable In a preclinical study, LOXO-783 (LOX-22783) treatment led to growth inhibition in breast cancer cell lines harboring PIK3CA H1047R, and led to tumor regression in cell line xenograft and patient-derived xenograft (PDX) models (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P142). detail...