Top 5 Target	Count

Cbl-b(E3 ubiquitin-protein ligase CBL-B)	2
IRF5(interferon regulatory factor 5)	1
PKCθ(Protein kinase C theta)	1
MALT1(Mucosa-associated lymphoid tissue lymphoma translocation protein 1)	1

Drugs associated with HotSpot Therapeutics, Inc.

HST-1011

Target

Cbl-b

Mechanism

Cbl-b inhibitors

Active Org.

HotSpot Therapeutics, Inc.Startup

Originator Org.

HotSpot Therapeutics, Inc.Startup

Active Indication

Advanced Malignant Solid Neoplasm [+4]

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date-

CBL B inhibitor (HotSpot Therapeutics)

Target

Cbl-b

Mechanism

Cbl-b inhibitors

Active Org.

HotSpot Therapeutics, Inc.Startup

Originator Org.

HotSpot Therapeutics, Inc.Startup

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date-

IRF5

Target

IRF5

Mechanism

IRF5 inhibitors

Active Org.

AbbVie, Inc. [+1]

Originator Org.

HotSpot Therapeutics, Inc.Startup [+1]

Active Indication

Myositis [+3]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date-

Clinical Trials associated with HotSpot Therapeutics, Inc.

NCT05662397 / RecruitingPhase 1/2

An Open Label, Phase 1/2 Study of HST-1011 Given as Monotherapy and in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors

This is a Phase 1/2 study of HST-1011, a CBL-B inhibitor, being developed for the treatment of patients with advanced solid tumors, who relapsed while on or are refractory to approved anti-PD(L)1 therapies or other standard of care.

Start Date15 Mar 2023

Sponsor / Collaborator

HotSpot Therapeutics, Inc.Startup

100 Clinical Results associated with HotSpot Therapeutics, Inc.

0 Patents (Medical) associated with HotSpot Therapeutics, Inc.

Literatures (Medical) associated with HotSpot Therapeutics, Inc.

13 Feb 2024·Journal of Chemical Theory and Computation

A Fast, Convenient, Polarizable Electrostatic Model for Molecular Dynamics

Article

Author: Schauperl, Michael ; Mobley, David L ; Wang, Liangyue ; Bayly, Christopher ; Gilson, Michael K

We present an efficient polarizable electrostatic model, utilizing typed, atom-centered polarizabilities and the fast direct approximation, designed for efficient use in molecular dynamics (MD) simulations. The model provides two convenient approaches for assigning partial charges in the context of atomic polarizabilities. One is a generalization of RESP, called RESP-dPol, and the other, AM1-BCC-dPol, is an adaptation of the widely used AM1-BCC method. Both are designed to accurately replicate gas-phase quantum mechanical electrostatic potentials. Benchmarks of this polarizable electrostatic model against gas-phase dipole moments, molecular polarizabilities, bulk liquid densities, and static dielectric constants of organic liquids show good agreement with the reference values. Of note, the model yields markedly more accurate dielectric constants of organic liquids, relative to a matched nonpolarizable force field. MD simulations with this method, which is currently parametrized for molecules containing elements C, N, O, and H, run only about 3.6-fold slower than fixed charge force fields, while simulations with the self-consistent mutual polarization average 4.5-fold slower. Our results suggest that RESP-dPol and AM1-BCC-dPol afford improved accuracy relative to fixed charge force fields and are good starting points for developing general, affordable, and transferable polarizable force fields. The software implementing these approaches has been designed to utilize the force field fitting frameworks developed and maintained by the Open Force Field Initiative, setting the stage for further exploration of this approach to polarizable force field development.

14 Apr 2023·Cancer Research

Abstract CT251: Phase 1/2 study of HST-1011, an oral CBL-B inhibitor, alone and in combination with anti-PD1 in patients with advanced solid tumors

Author: Rodón, Jordi ; Agarwal, Parul ; Reilly, Timothy ; Friedman, Claire ; Danaee, Hadi ; Sun, Huadong ; Wright, Emma ; Luke, Jason ; Friedman, Evan ; Patel, Manish ; Barth, Carolin ; Sanborn, Rachel E. ; Kelley, Heather ; Peterson, Connacht ; Redig, Amanda J.

AbstractBackground: The E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a master negative regulator of the immune system and thus an attractive target to address suboptimal outcomes to immune checkpoint inhibitors (ICI). CBL-B controls T-cell/NK cell activation and co-stimulatory pathways, including the signaling threshold for T-cell receptor (TCR) activation. CBL-B inhibition uncouples TCR stimulation from the requirement for CD28 co-stimulation while reducing T-cell susceptibility to immunosuppression mediated by PD1, immunosuppressive cytokines, and Treg cells. Accordingly, targeting CBL-B may enable immune activation even in tumors with low antigen levels, low intratumoral inflammation, inadequate co-stimulation and/or active immunosuppression associated with poor response/resistance to existing ICIs. HST-1011 is a novel, potent, selective, orally bioavailable allosteric small molecule CBL-B inhibitor that has been shown to robustly increase anti-tumor immunity in vitro and in vivo, including in model systems where other ICIs have minimal effect.Methods: SOLAR1 (NCT05662397) is a first-in-human, multicenter Ph1/2 trial investigating safety and tolerability (primary endpoint), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy (secondary endpoints) of HST-1011 monotherapy and an HST-1011/PD1 inhibitor combination. HST-1011 will be given orally while the PD1 inhibitor cemiplimab will be administered intravenously.Eligibility: Patients with advanced solid tumors and progression on standard of care diagnosed with a) tumor types for which PD-(L)1 therapies are approved with documented PD-(L)1 refractory/resistant disease, including patients with best response of stable disease for ≥ 6 months while on a PD-(L)1, OR b) selected tumor types in which patients may be naïve to anti-PD(L)1 (platinum-resistant ovarian cancer, metastatic castration-resistant prostate cancer without bony lesions, rectal cancer, anal cancer).Study Design: Ph1, Part A1: HST-1011 monotherapy dose escalation, utilizing a Bayesian optimal interval design (BOIN). Optional dosing cohorts will assess alternative dosing strategies. Ph1, Part A2: HST-1011 monotherapy dose optimization with up to 4 cohorts utilizing dose(s)/schedule(s) deemed safe in Part A1 but focused on histology-specific patient populations to generate additional PK, PD, and efficacy data within a potential Recommended Phase 2 Dose (RP2D) range. Ph1, Part B: HST-1011 dose escalation in combination with cemiplimab, as in Part A1 with a BOIN design and optional dosing cohorts.Biomarkers: Target engagement and PD will be assessed via a) serial monitoring of cytokines/chemokines and transcriptional profiles; b) peripheral immune cell profiling; and c) in-depth analysis of screening and on-treatment tumor biopsies. The study is open with competitive enrollment.Citation Format: Jason Luke, Rachel E. Sanborn, Jordi Rodón, Manish Patel, Parul Agarwal, Evan Friedman, Connacht Peterson, Heather Kelley, Emma Wright, Hadi Danaee, Huadong Sun, Carolin Barth, Timothy Reilly, Amanda J. Redig, Claire Friedman. Phase 1/2 study of HST-1011, an oral CBL-B inhibitor, alone and in combination with anti-PD1 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT251.

14 Apr 2023·Cancer Research

Abstract LB337: Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells

Author: Danaee, Hadi ; Bi, Yingzhi ; Carson, Ken ; Qi, Yilin ; Jaeger, Samira ; Greco, David ; Kuai, Jun ; Wang, Fang ; Harriman, Geraldine ; Reilly, Timothy

AbstractThe E3 ubiquitin ligase CBL-B is a master regulator of effector T cells through its downstream regulation of T-cell receptor and co-stimulatory stimulation, but it has also been shown to play a negative feedback role in NK cells. CBL-B depletion enhances the production of IFNγ and the cytotoxicity of activated NK cells. Similar to the effect of depleting CD8 T cells in mice, depletion of NK cells abolishes the tumor growth delay observed in Cbl-b-/- mice. With emerging data supporting the potential role of exogenous NK cells in anti-tumor immunity, inhibition of CBL-B represents a promising approach to enhance both adaptive and innate immunity for cancer immunotherapy. Using one of our small molecules, allosteric CBL-B inhibitors, HOT-A, we demonstrated that CBL-B inhibition enhanced NK activation, IFNγ production and granzyme B secretion in response to the various stimulation conditions, including cytokines (such as IL-15 and IL12 + IL-18) and stimulatory receptors (such as NKp30 and NKG2D + CD244). NK cell proliferation was also enhanced in the presence of HOT-A. Single cell analysis further suggested that HOT-A increased NK polyfunctional cytokine expression during IL-12 + IL-18 activation. In a coculture system of NK cells and K562 target cells, HOT-A dose-dependently promoted primary human NK cell activation, cytokine production and cytotoxicity in the K562 cells. In the in vivo CT-26 tumor model, granzyme B+ NK cells in the TIL were significantly increased in the HOT-A treated tumor bearing mice and NK function gene signature was also increased by Nanostring analysis, suggesting an enhanced NK function in the tumor microenvironment. Taken together, the pre-clinical data presented here demonstrate that our CBL-B inhibitor enhances NK cell function in vitro and in vivo, suggesting that its enhancement of anti-tumor immunity may be driven through both effector T cell and NK cell-driven biology.Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, David Greco, Samira Jaeger, Ken Carson, Hadi Danaee, Timothy Reilly, Geraldine Harriman, Fang Wang. Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB337.

News (Medical) associated with HotSpot Therapeutics, Inc.

23 Oct 2024

·www.prnewswire.com

HotSpot Therapeutics Presents Preclinical Data from MALT1 CBM Signalosome Glue Program at 36th EORTC-NCI-AACR Symposium

BOSTON, Oct. 23, 2024 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present preclinical data from the Company's mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR Symposium. MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company's proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1's protease function. "Our proprietary Smart Allostery™ platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1's scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021's potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway." The presentation describes preclinical data for HST-1021, HotSpot's MALT1 CBM signalosome glue development candidate: In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity. In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021's potential for the treatment of NF-kB-driven solid tumors. About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is a clinical-stage biotechnology company that is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AACR

09 Oct 2024

·www.prnewswire.com

HotSpot Therapeutics to Present Preclinical Data from MALT1 CBM Signalosome Glue Program at 36th EORTC-NCI-AACR Symposium

BOSTON, Oct. 9, 2024 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present preclinical data from the Company's mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR Symposium, taking place October 23-25, 2024, in Barcelona, Spain. Presentation details are as follows: Title: Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of NFkB driven solid tumors Poster Session: Molecular Targeted Agents Session Date and Time: Wed., Oct. 23, 2024, 12:00-19:00 CEST Abstract Number: 105 About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is a clinical-stage biotechnology company that is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AACR

04 Oct 2024

·www.prnewswire.com

HotSpot Therapeutics to Present Additional Phase 1 Biomarker Data on Novel CBL-B Inhibitor HST-1011 at 2024 Society for Immunotherapy of Cancer Annual Meeting

BOSTON, Oct. 4, 2024 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present additional Phase 1 clinical biomarker data for HST-1011, an investigational oral, selective inhibitor of Casitas B-lineage lymphoma proto-oncogene (CBL-B), in a poster presentation at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting, taking place November 6-10, 2024, in Houston, Texas. The poster will showcase exploration of potential clinical biomarkers that correlate with signs of clinical activity in patients from the ongoing Phase 1 monotherapy dose-escalation study of HST-1011. Presentation details are as follows: Title: Peripheral Blood and Tumor Gene Expression as Biomarkers and Potential Predictors of Clinical Outcome with HST-1011, an Oral CBL-B Inhibitor Session Date and Time: Sat., Nov. 9, 2024, 9:00 AM-8:30 PM CT Location: Exhibit Halls A & B, George R. Brown Convention Center Abstract Number: 1310 About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is a clinical-stage biotechnology company that is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

ImmunotherapyPhase 1AACR

100 Deals associated with HotSpot Therapeutics, Inc.

100 Translational Medicine associated with HotSpot Therapeutics, Inc.

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Pipeline Snapshot as of 26 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Phase 2 Clinical

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

HST-1011 ( Cbl-b )	Advanced Malignant Solid Neoplasm More	Phase 2 Clinical
CBL B inhibitor (HotSpot Therapeutics) ( Cbl-b )	Neoplasms More	Preclinical
HST-1021 ( MALT1 )	Neoplasms More	Preclinical
PKC theta antagonists (HotSpot Therapeutics) ( PKCθ )	Autoimmune Diseases More	Preclinical
IRF5 ( IRF5 )	Systemic Lupus Erythematosus More	Preclinical

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