Jul 2026· Expert Opinion on Therapeutic Patents· Vol 36, pp. 865-891· 0 citations· 28 references
Medicine
TL;DR
This review evaluates patents of PI3Kα mutant-selective inhibitors disclosed between 2021 and 2025 and examines the binding modes across two distinct allosteric domains: an H1047R-specific pocket (exemplified by Eli Lilly's inhibitors) and a pan-mutant cryptic site (engaged by RLY-2608 and STX-478).
Abstract
INTRODUCTION
Oncogenic PIK3CA mutations drive numerous solid tumors, rendering PI3Kα a key therapeutic target. However, conventional ATP-competitive inhibitors are severely limited by dose-limiting metabolic toxicities caused by wild-type PI3Kα inhibition. To circumvent these limitations, the drug discovery landscape is rapidly shifting toward mutant-selective allosteric inhibitors designed to spare physiological signaling and expand the therapeutic window.
AREAS COVERED
Utilizing the Cortellis Drug Discovery Intelligence (CDDI) database, this review evaluates patents of PI3Kα mutant-selective inhibitors disclosed between 2021 and 2025. The analysis focuses on structural features, pharmacological profiles, and medicinal chemistry strategies employed to achieve high selectivity for oncogenic mutants over the wild-type enzyme. Specifically, we examine the binding modes across two distinct allosteric domains: an H1047R-specific pocket (exemplified by Eli Lilly's inhibitors) and a pan-mutant cryptic site (engaged by RLY-2608 and STX-478).
EXPERT OPINION
Mutant-selective allosteric inhibitors achieve selectivity by targeting mutant residues or exploiting unique protein conformational dynamics. The rapidly diversifying patent landscape provides broader opportunities for the discovery of superior inhibitors. Furthermore, development of allosteric inhibitor based PROTACs is discussed as a promising frontier for enhancing therapeutic precision. Ultimately, deeper understanding of evolving resistance mechanisms provides the design principles required to develop next-generation PI3Kα therapeutics capable of overcoming clinical resistance.
A number of lead candidates with strong EGFR inhibitory potential, promising pharmacokinetic profiles, and mutant selectivity were successfully identified by the integrated computational approach.
M. Kendre, Sachin S. Bhusari, Pravin S. Wakte· Journal of Pharmaceutical In...· 0 citations
INTRODUCTION
Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of DNA damage repair and an attractive therapeutic target for homologous recombination-deficient malignancies. The development of selective PARP1 inhibitors has been driven by the need to reduce the hematological toxicities associated with nonselective PARP inhibition.
AREA COVERED
This review summarizes patents and recent advances in selective PARP1 inhibitors reported from 2021 to the present. Particular emphasis is placed on the structural evolution of AZD5305-derived compounds and emerging quinazolinone- and isoquinolinone-based chemotypes. Key design strategies, including adenine-pocket optimization, linker remodeling, conformational restriction, and scaffold diversification, are discussed together with their impact on PARP1 selectivity and biological activity.
EXPERT OPINION
Selective PARP1 inhibition has become a major focus of innovation in the PARP field. Current patents indicate that adenine-pocket engagement, linker optimization, conformational control, and scaffold innovation are central to achieving high PARP1 selectivity and represent important directions for future intellectual property development. Despite significant progress, the disclosed chemical space remains relatively limited, highlighting opportunities for further scaffold diversification and differentiated patent strategies. These advances are expected to facilitate the development of next-generation PARP1-targeted therapeutics with improved safety profiles and broader clinical potential.
Jilong Duan, Yanjing Duan, Dongling Gu et al.· Expert Opinion on Therapeuti...· 0 citations
p21-activated kinase 4 (PAK4), a Group II PAK family member, is a therapeutically relevant candidate target in cancer, metabolic disease, and tissue injury. However, translation of PAK4 biology into drug candidates has been constrained by the conserved ATP-binding architecture of PAK isoforms, unfavorable pharmacokinetic profiles, and suboptimal clinical efficacy. We summarize the evolution of ATP-competitive Type I inhibitors, Type I½ back-pocket inhibitors, allosteric modulators, and PROTAC degraders, and compare representative compounds using potency, isoform selectivity, cellular activity, oral bioavailability, and development status. Particular emphasis is placed on structural determinants of selectivity, including the αC-helix-dependent hydrophobic back pocket, the inward Asp444/Asp458 floor pocket arrangement, and peripheral microenvironment differences that distinguish PAK4 from Group I PAKs. We also summarize the potential ADMET liabilities-such as pronounced efflux, metabolic instability, and poor oral bioavailability-that may arise from structural modifications aimed at enhancing PAK4 selectivity, and discuss rational optimization strategies to navigate these inherent barriers. Finally, we discuss clinical lessons from PF-3758309 and KPT-9274/padnarsertib and highlight how allosteric inhibitors and PROTAC degraders may help address limitations of conventional ATP-site inhibitors.
Ruiqing Shi, Xue Feng, Zixu Wang et al.· European journal of medicina...· 0 citations
Human epidermal growth factor receptor 2 (HER2) is an oncogenic receptor tyrosine kinase in breast cancer and other malignancies. A subset of HER2-positive tumours expresses 611-CTF-p95HER2, a tumour-specific, hyperactive truncated isoform associated with metastasis and treatment resistance that lacks most of the extracellular domain targeted by conventional HER2-directed antibodies. We previously developed NAZ-mAb (formerly known as Oslo-2), a monoclonal antibody against 611-CTF-p95HER2. Here, we describe a computational antibody-engineering workflow for designing variants of NAZ-mAb. Starting from the sequence alone, we modeled the NAZ-mAb–611-CTF-p95HER2 complex, generated a combinatorial mutational landscape using FoldX 5.0, and prioritized candidate variants using predicted interaction energy and developability criteria. Two variants representing distinct design strategies were selected for validation: an aromatic double mutant, NAZ-mAb v1 (L:S31W/L:H107W), and a conservative single mutant, NAZ-mAb v2 (L:S31M). Both variants were successfully expressed as recombinant IgGs; NAZ-mAb v2 achieved a five-fold higher recombinant expression yield than parental NAZ-mAb, while both variants retained antigen binding with a higher apparent signal than the parental antibody in indirect ELISA. However, Biacore two-state kinetic analysis revealed weaker affinities than the parental antibody (KD NAZ-mAb v1: 32.6 nM, NAZ-mAb v2: 9.45 nM vs. parental NAZ-mAb: 5.33 nM). These findings show that the computational workflow can generate experimentally tractable, antigen-engaging NAZ-mAb variants, while also highlighting the limitations of fixed-backbone interaction-energy ranking as a predictor of binding affinity and yield. This study provides a practical framework for computationally driven, developability-aware antibody optimization in the absence of experimental structural data.
P. Rawat, J. Kyte, Victor Greiff et al.· bioRxiv· 0 citations
This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.
FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML); mutations within FLT3, specifically ITD lesions and TKD point mutations, promote proliferation and are associated with poor prognosis. Although FLT3 inhibition is central to AML therapy, resistance, particularly via D835 activation-loop variants and the F691L gatekeeper substitution, limits durability. Among the major therapeutic classes, type I inhibitors bind the active (DFG-in) conformation, whereas type II inhibitors stabilize the inactive (DFG-out) state. In contrast, irreversible covalent inhibitors target reactive cysteine residues within the kinase domain. Collectively, these approaches represent complementary therapeutic strategies with distinct resistance liabilities and structural design considerations. This review integrates structural biology with medicinal-chemistry evidence across type I, type II, irreversible, and dual-modality FLT3 inhibitors, analyzing how hinge contacts, back-pocket occupancy, and warhead placement govern activity across wild-type and mutant FLT3. We map resistance-defining residues (e.g. F691, D835, N676, N701) and design tactics to preserve potency against resistant variants. We also summarize combination therapy that augments selective FLT3 blockade and outline PROTAC approaches that induce FLT3 degradation, positioning these modalities as alternatives when single-molecule polypharmacology is constrained. Finally, we catalogue dual-target FLT3 chemotypes, highlighting examples that retain activity against F691L and D835 in cellular systems and xenografts. Overall, this review provides a section-by-section guide covering FLT3 structure and mutation hotspots, analyses of type I, type II, and irreversible inhibitors, dual-modality designs, combinations, PROTACs, and future perspectives. It links binding mode, covalent engagement, and second-target selection to recurrent resistance biology to guide more resilient FLT3-targeted therapies for high-risk AML.
Fatma M Elmenier, Eman M. E. Dokla, Nermin Samir et al.· RSC Advances· 0 citations
